Selective octahydro-cyclopenta[c]pyrrole negative modulators of nr2b

ABSTRACT

Compounds that selectively negatively modulate NMDA receptors containing an NR1/NR2B subunit, pharmaceutical compositions comprising the compounds, and methods of treating a disease using the compounds are disclosed.

PRIORITY

This application is a continuation of U.S. patent application Ser. No.15/360,824, filed Nov. 23, 2016, which is a divisional of U.S. patentapplication Ser. No. 14/498,462, filed Sep. 26, 2014, which claimspriority to provisional application No. 61/883,050, filed Sep. 26, 2013,the entire disclosures of all of which are hereby incorporated byreference.

FIELD

The present disclosure relates to compounds that selectively negativelymodulate the activity of an NR1/NR2B receptor.

BACKGROUND

The NMDA receptor is arguably an important signaling mechanism in thehuman brain. The brain processes a complex array of information to allowhumans to function, storing information from the past and analyzing thisinformation in the context of the present to respond and plan for thefuture. These incredibly complex computations are mediated at themolecular level by the continual adjustment of the strength of synapses,the nodes for communication between nerve cells (estimated at about 60trillion in the human brain).

Glutamate is the major excitatory neurotransmitter in the brain,utilized at 80% of these synapses. NMDA receptors are one of threeclasses that mediate synaptic transmission using glutamate. NMDAreceptors play a critical role in regulating the strength of synapses,that is, in regulating synaptic plasticity. Thus, the NMDA receptor isat the molecular core of brain function, and in particular the cognitivefunctions of learning and memory. These facts underlie the tremendoustherapeutic utility of modulating NMDA receptor function with new drugsto treat a broad range of neuropsychiatric disease and cognitivedysfunction.

The molecular basis of NMDA receptor function is increasingly wellunderstood. The NMDA receptor is composed of four protein subunits, twoNR1 subunits and two NR2 subunits. An NR1 subunit derived from a singlegene is ubiquitously expressed throughout the brain and is common to allNMDA receptors. However, the four different NR2 subunits, NR2A-D, arederived from separate genes that are differentially expressed indifferent brain regions and by distinct populations of neurons within aparticular region. Furthermore, individual neurons may express more thanone NR2 subunit and individual NMDA receptors expressed by such neuronsmay contain two of the same NR2 subunits (for example, 2 NR2B subunits)or two different subunits (one NR2A and one NR2B subunit). Therefore, adrug that selectively modulates the activity of one NR2 subunit may doso at receptors that express two of the targeted subunits, or only oneof the targeted subunits. Thus there is a need for new treatments fordiseases related to the NR1/NR2B receptor.

SUMMARY

In an aspect, compounds of Formula I are described:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers or stereoisomers thereofwherein:L₁ is straight or branched C₂-C₄ alkyl substituted with one or moresubstituents selected from the group consisting of OH, D, OR₁₀, NH₂,NHR₁₀, and N(R₁₀)(R_(10′)), provided that no more than one oxygen ornitrogen is attached to any carbon; orL₁ is selected from the group consisting of —CO—C₁-C₂alkylenyl-,—S(O)₂—, —S(O)₂NH—, —C(O)NH—, —C(O)NR₁₀—,—C₁-C₃alkylenyl-C(O)—C₁-C₃alkylenyl-, and a bond, wherein theC₁-C₂alkylenyl or C₁-C₃alkylenyl is optionally substituted with C₁-C₄alkyl;

-   -   each R₁₀ and R_(10′) is independently selected from the group        consisting of H; O—C₁-C₅ alkyl; C₁-C₆ alkyl optionally        substituted with one or more substituents selected from the        group consisting of OH, O—C₁-C₅ alkyl, —OP(O)(OH)₂, OP(O)O₂        ⁻²M₂, —OC(O)alkyl, —OC(O)Oalkyl, aryl, and heteroaryl; and        cycloalkyl optionally substituted with one or more substituents        selected from the group consisting of OH and O—C₁-C₅ alkyl;    -   provided that no more than one oxygen is attached to any carbon        of R₁₀ and R_(10′);    -   M is a monovalent metal cation;    -   or R₁₀ and R_(10′), together with the nitrogen to which they are        attached, may form a heterocycle;

R₁ is aryl or heteroaryl, both of which optionally substituted with oneor more substituents selected from the group consisting of OH, CN,halogen, —O—R₁₀, —OP(O)(OH)₂, OP(O)O₂ ⁻²M₂, —SH, —S—R₁₀, C₁-C₅ alkyl,branched alkyl, —C₁-C₆haloalkyl, NH₂, NHR₁₀, —C₁-C₆hydroxyalkyl,N(R₁₀)(NR_(10′)), —NHS(O)₂R₁₀, —O-alkylaryl, —O—(CH₂)_(n)—C(O)-aryl, andNHCOR₁₀; M is a monovalent metal cation; or

R₁ is cycloalkyl;X is selected from the group consisting of H, halogen, OH, O—C₁-C₆alkyl, O-branched alkyl, C₁-C₅ straight alkyl and C₁-C₅ branched alkyl;Y and Y′ are independently H, F, or methyl;L₂ is —(CH₂)_(n)— or —(CHR₁₁)_(n)—, or a bond;

-   -   Each R₁₁ is independently selected from the group consisting of        H, —C₁-C₅ alkylenyl-, —C(O)—C₁-C₅alkylenyl-, and        -alkylenyl-CO-alkylenyl-;        R₂ is C₃-C₈cycloalykl; C₃-C₈heterocyclcyl, phenyl, naphthyl,        heteroaryl, or bicyclic heteroaryl, each of which is optionally        substituted with one or more substituents selected from the        group consisting of halogen, OH, C₁-C₆alkyl, OR₁₀, CN, NH₂,        NHR₁₀, N(R₁₀)(R_(10′)), SH, SR₁₀, SOR₁₀, SO₂R₁₀, SO₂NHR₁₀,        SO₂N(R₁₀)(R_(10′)), CONH₂, CONR₁₀, and CON(R₁₀)(R_(10′)); and        n is 1, 2, or 3.

In another aspect, compounds of Formula II are described:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereofwherein:L₁ is straight or branched C₁-C₅ alkyl optionally substituted with oneor more substituents selected from the group consisting of H, OH, OR₁₀,NH₂, NHR₁₀, and N(R₁₀)(R_(10′)) provided that no more than one oxygen ornitrogen is attached to any carbon; orL₁ is selected from the group consisting of —C(O)—,—C(O)—C₁-C₃alkylenyl-, —S(O)₂—, —S(O)₂NH—, —CONH—, —CON(R₁₀)—, and abond;

-   -   Each R₁₀ and R_(10′) is independently selected from the group        consisting of H; C₁-C₆ alkyl optionally substituted with one or        more substituents selected from the group consisting of OH,        O—C₁-C₅ alkyl, OPO₃ ⁻²M₂, OP(O)(OH)₂, OCOalkyl, and OC(O)Oalkyl        where M is a monovalent metal cation; and cycloalkyl optionally        substituted with one or more substituents selected from the        group consisting of OH and O—C₁-C₅ alkyl provided that no more        than one oxygen is attached to any carbon; or R₁₀ and R_(10′),        together with the nitrogen to which they are attached, may form        a heterocycle;        R₁ is aryl or heteroaryl, both of which optionally substituted        with one or more substituents selected from the group consisting        of OH, CN, halogen, O—R₁₀, OPO₃ ⁻²M₂, OP(O)(OH)₂, SH, S—R₁₀,        C₁-C₅ alkyl, branched alkyl, NH₂, NHR₁₀, N(R_(10′))(NR_(10′)),        and NHCOR₁₀ where M is a monovalent metal cation; or        R₁ is cycloalkyl;        Y and Y′ are independently H, F or methyl;        L₂ is a bond, (CH₂)_(n) or (CHR₁₁)_(n);    -   Each R₁₁ is independently selected from the group consisting of        H, —C₁-C₅ alkylenyl-, —CO—C₁-C₅alkylenyl-, and        -alkylenyl-CO-alkylenyl-;        R₂ is phenyl, naphthyl, heteroaryl or bicyclic heteroaryl, each        of which is optionally substituted with one or more substituents        selected from the group consisting of halogen, OH, OR₁₀, CN,        NH₂, NHR₁₀, N(R₁₀)(R_(10′)), SH, SR₁₀, —S(O)R₁₀, —S(O)₂R₁₀,        —S(O)₂NHR₁₀, —S(O)₂N(R₁₀)(R_(10′)), —C(O)NH₂, —C(O)NR₁₀, and        —C(O)N(R₁₀)(R_(10′)); and        n is 1, 2, or 3.

In another aspect, compounds of Formula III are described:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereofwherein:L₁ is straight or branched C₁-C₅ alkyl optionally substituted with oneor more substituents selected from the group consisting of H, OH, OR₁₀,NH₂, NHR₁₀, and N(R₁₀)(R_(10′)) provided that no more than one oxygen ornitrogen is attached to any carbon; orL₁ is selected from the group consisting of —C(O)—, —C(O)O—,—C(O)—C₁-C₃alkylenyl-, —S(O)₂—, —S(O)₂NH—, —C(O)NH—, —C(O)NR₁₀—, and abond;

-   -   Each R₁₀ and R_(10′) is independently selected from the group        consisting of H; C₁-C₆ alkyl optionally substituted with one or        more substituents selected from the group consisting of OH,        O—C₁-C₅ alkyl, OPO₃ ⁻²M₂, OP(O)(OH)₂, OC(O)alkyl, and        OC(O)Oalkyl where M is a monovalent metal cation; and cycloalkyl        optionally substituted with one or more substituents selected        from the group consisting of OH and O—C₁-C₅ alkyl provided that        no more than one oxygen is attached to any carbon; or R₁₀ and        R_(10′), together with the nitrogen to which they are attached,        may form a heterocycle;        R₁ is aryl or heteroaryl, both of which optionally substituted        with one or more substituents selected from the group consisting        of OH, CN, halogen, O—R₁₀, OPO₃ ⁻²M₂, OP(O)(OH)₂, SH, S—R₁₀,        C₁-C₅ alkyl, branched alkyl, NH₂, NHR₁₀, N(R₁₀)(NR_(10′)), and        NHCOR₁₀ where M is a monovalent metal cation; or        R₁ is straight or branched C₁-C₆ alkyl or cycloalkyl;        X is selected from the group consisting of H, halogen, OH,        O—C₁-C₆ alkyl, O-branched alkyl, C₁-C₅ straight alkyl and C₁-C₅        branched alkyl;        L₂ is —(CH₂)_(n)— or —(CHR₁₁)_(n)—, or a bond;    -   Each R₁₁ is independently selected from the group consisting of        H, —C₁-C₅ alkylenyl-, —CO—C₁-C₅alkylenyl-, and        -alkylenyl-CO-alkylenyl-;        R₂ is phenyl, naphthyl, heteroaryl or bicyclic heteroaryl, each        of which is optionally substituted with one or more substituents        selected from the group consisting of halogen, OH, OR₁₀, CN,        NH₂, NHR₁₀, N(R₁₀)(R_(10′)), SH, SR₁₀, —S(O)R₁₀, —S(O)₂R₁₀,        —S(O)₂NHR₁₀, —S(O)₂N(R₁₀)(R_(10′)), —C(O)NH₂, —C(O)NHR₁₀, and        CON(R₁₀)(R_(10′)); and        n is 1, 2, or 3.

The present disclosure further pertains to compounds that selectivelymodulate the activity of NMDA receptors that contain an NR2B subunit,which encompasses receptors containing two NR2B subunits or one NR2Bsubunit in combination with one other NR2 subunit (ie., NR2A/NR2B,NR2B/NR2C, or NR2B/NR2D receptors). Such compounds may either increaseor decrease the activity of NR2B-containing NMDA receptors. The presentinvention also pertains to the therapeutic uses of such compounds. Alsodescribed are pharmaceutical formulations comprising at least adisclosed compound.

Also described herein are methods of treating a disease susceptible totreatment with a disclosed compound in a patient in need thereof byadministering to the patient an effective amount of a disclosedcompound. Such diseases include, without limitation, neurologicaldysfunction such as Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis, multiple sclerosis, and seizuredisorders; emotional disorders; depression; bipolar disorder;obsessive-compulsive disorder; and other anxiety disorders.

Compounds or pharmaceutical compositions of the present invention may beused to treat individuals that experience dysfunction caused by abnormalbrain development, including but not limited to those suffering fromautism and autism spectrum disorders, Fragile X syndrome, Rett Syndrome,Angelman syndrome, tuberous sclerosis, Down's syndrome and other formsof mental retardation.

The invention further pertains to pharmaceutical compositions thatcomprise an effective amount of a disclosed compound and apharmaceutically acceptable carrier. The compositions are useful fortreating or preventing a disease or disorder. The invention includes adisclosed compound provided as a pharmaceutically acceptable prodrug,hydrate, salt, stereoisomer, or mixtures thereof.

The invention also includes the use of a compound or pharmaceuticalcomposition as described herein in the manufacture of a medicament forthe treatment of a disease mediated by the NR1/NR2B receptor.

The invention also includes any compound described herein or apharmaceutically acceptable salt thereof for use in treating a diseasemediated by the NR1/NR2B receptor.

DETAILED DESCRIPTION

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g. an alkyl group) can (but is not required to) bebonded other substituents (e.g. heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e. a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 2 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to, —H,-halogen, —O—C₁-C₆alkyl, C₁-C₆alkyl, —OC₁-C₆alkenyl, —OC₁-C₆alkynyl,—C₁-C₆alkenyl, —C₁-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆alkyl,—C(O)C₁-C₆alkyl, —OC(O)OC₁-C₆alkyl, NH₂, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂,—S(O)₂—C₁-C₆alkyl, —S(O)NHC₁-C₆alkyl, and S(O)N(C₁-C₆alkyl)₂. Thesubstituents can themselves be optionally substituted. Furthermore whencontaining two fused rings the aryl groups herein defined may have anunsaturated or partially saturated ring fused with a fully saturatedring. Exemplary ring systems of these aryl groups include indanyl,indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 10 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, or S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl,and derivatives thereof. Furthermore when containing two fused rings thearyl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine, and dihydrobenzoxanyl.

“C₁-C₃ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-3 carbon atoms. Examples of a C₁-C₃alkyl groupinclude, but are not limited to, methyl, ethyl, propyl and isopropyl.

“C₁-C₅ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-5 carbon atoms. Examples of a C₁-C₅alkyl groupinclude, but are not limited to, methyl, ethyl, propyl, butyl, pentyl,isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.

Alkyl is generally lower alkyl, or C₁-C₆ alkyl. Examples of a C₁-C₆alkyl group include, but are not limited to, methyl, ethyl, propyl,butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl,isopentyl, neopentyl, and isohexyl.

“Alkylenyl” as herein defined refers to groups of general formula—(CH₂)_(n)— where n is an integer from 1 to 6. Suitable examples ofalkylenyl groups include methylenyl, ethylenyl, and propylenyl.

The term “haloalkyl” refers to straight or branched saturatedhydrocarbon chains containing 1-5 carbon atoms which are substituted atleast one of the carbon with halogen groups such fluorine, chlorine,bromine, iodide. Examples of haloalkyl groups as herein defined includewithout limitation trifluoromethyl, tribromomethyl, and1,1,1-trifluoroethyl.

The term “hydroalkyl” refers to straight or branched saturatedhydrocarbon chains containing 1-5 carbon atoms which are substituted atleast one of the carbon with the hydroxyl group.

The term “-alkylaryl” refers to aryl groups connected to an adjacentC1-C6alkyl wherein the linkage is located at the alkyl end. Forexamples, groups such as benzyl, phenylethyl, or mesitylenyl.

“Cycloalkyl” means monocyclic saturated carbon rings containing 3-18carbon atoms. Examples of cycloalkyl groups include, withoutlimitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,10sethio[2.2.2]octanyl, or 10sethio[2.2.2]octenyl.

“Heterocyclyl” or “heterocycloalkyl” or “heterocycle” monocyclic ringscontaining carbon and heteroatoms taken from oxygen, nitrogen, or sulfurand wherein there is not delocalized it electrons (aromaticity) sharedamong the ring carbon or heteroatoms; heterocyclyl rings include, butare not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, andhomotropanyl.

“Spirocycle” means bicyclic ring system with both rings cnnected througha single atom. The ring can be different in size, nature, or identical.Examples include spiropentane, spriohexane, spiroheptane, spirooctane,spirononane, or spirodecane.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, 10sethionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

The term “monovalent metal cation” refers to atomic elements thatpositively charged (atoms which have more protons than electrons becausethey have lost electrons). Examples of metal cations include, withoutlimitation, monovalent metal and metalloids of the periodic table. Thesemetal cations include monovalent alkaline metals such L₁, K, Na, Rb, orCs, monovalent transition metals such as Cu, Au, or Ag.

The term “stereoisomers” refers to the set of compounds which have thesame number and type of atoms and share the same bond connectivitybetween those atoms, but differ in three dimensional structure. The term“stereoisomer” refers to any member of this set of compounds.

The term “diasteromers” refers to the set of stereoisomers which cannotbe made superimposable by rotation around single bonds. For example,cis- and trans-double bonds, endo- and exo-substitution on bicyclic ringsystems, and compounds containing multiple stereogenic centers withdifferent relative configurations are considered to be diasteromers. Theterm “diasteromer” refers to any member of this set of compounds. Insome examples presented, the synthetic route may produce a singlediateromer or a mixture of diasteromers. In some cases these diateromerswere separated and in other cases a wavy bond is used to indicate thestructural element where configuration is variable.

The term “enantiomers” refers to a pair of stereoisomers which arenon-superimposable mirror images of one another. The term “enantiomer”refers to a single member of this pair of stereoisomers. The term“racemic” refers to a 1:1 mixture of a pair of enantiomers.

The term “tautomers” refers to a set of compounds that have the samenumber and type of atoms, but differ in bond connectivity and are inequilibrium with one another. A “tautomer” is a single member of thisset of compounds. Typically a single tautomer is drawn but it isunderstood that this single structure is meant to represent all possibletautomers that might exist. Examples include enol-ketone tautomerism.When a ketone is drawn it is understood that both the enol and ketoneforms are part of the invention.

A “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog,cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a coumpound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound. Furthermore, as used herein a prodrug is a drugwhich is inactive in the body, but is transformed in the body typicallyeither during absorption or after absorption from the gastrointestinaltract into the active compound. The conversion of the prodrug into theactive compound in the body may be done chemically or biologically(i.e., using an enzyme).

Compounds

In an embodiment, compounds of Formula I are described:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereof, wherein R₁, L₁, Y, Y′, X, L₂, andR₂ are described as above in formula I.

In one embodiment of the compounds of Formula I, R₁ is aryl orheteroaryl each of which is substituted with one or more substituentsselected from the group consisting of OH, halogen, OR₁₀, SH, SR₁₀, NH₂,NHR₁₀ and NHCOR₁₀.

In another embodiment of Formula I compounds, wherein R₁ is arylsubstituted with one substituent selected from the group consisting ofOH, halogen, OR₁₀, SH, SR₁₀, NH₂, NHR₁₀ and NHCOR₁₀.

In another embodiment of Formula I compounds, Y and Y′ are hydrogen.

In another embodiment of Formula I compounds, L₂ is a bond.

In another embodiment of Formula I compounds, n is 1.

In another embodiment of Formula I compounds, n is 2.

In another embodiment of Formula I compounds, R₂ is phenyl optionallysubstituted with one or more halogen, OH, OR₁₀, CN, NH₂, NHR₁₀,N(R₁₀)(R_(10′)), SH, SR₁₀, SOR₁₀, SO₂R₁₀, SO₂NHR₁₀, SO₂N(R₁₀)(R_(10′)),CONH₂, CONR₁₀, CON(R₁₀)(R_(10′)).

In another embodiment of Formula I compounds, R₂ is phenyl substitutedwith one or more halogen.

In another embodiment of Formula I compounds, L₁ is branched C₂-C₄ alkylsubstituted with one or more substituents selected from the groupconsisting of OH, OR₁₀, NH₂, NHR₁₀, and N(R₁₀)(R_(10′)) provided that nomore than one oxygen or nitrogen is attached to any carbon of L₁.

In another embodiment of Formula I compounds, L₁ is straight C₂-C₄ alkylsubstituted with one or more substituents selected from the groupconsisting of OH, OR₁₀, NH₂, NHR₁₀, and N(R₁₀)(R_(10′)) provided that nomore than one oxygen or nitrogen is attached to any carbon of L₁.

In another embodiment of the invention, compounds of Formula (Ia) aredisclosed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereof;wherein:

A, B, C, and D are independently N or CH;

X is CH or C;

Y is OH or O;

R₃ is H or CH₃;

n is 0, 1, or 2;

R is H, OH or R; and

R₁ is H or F.

In another embodiment of Formula Ia compounds, A, B, C, and D are CH.

In another embodiment of Formula Ia compounds, X and Y form a carbonyl.

In another embodiment of Formula Ia compounds, X is CH and Y is OH.

In another embodiment of Formula Ia compounds, R₃ is H.

In another embodiment of Formula Ia compounds, R is H.

In another embodiment of Formula Ia compounds, R is OH.

In another embodiment of Formula Ia compounds, n is 0.

In another embodiment of Formula Ia compounds, n is 1.

In another embodiment of Formula Ia compounds, n is 2.

In another embodiment of Formula Ia compounds, R₁ is H.

In another embodiment of Formula Ia compounds, R₁ is F.

In another embodiment of the invention, compounds of Formula (Ib) aredisclosed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereofwherein:

A, B, C, and D are independently N or CR_(x);

X is CH or C;

Y is OH or O;

R₃ is H;

n is 0, 1, or 2;

R is H, or CH₃; and

R_(x) is H, C₁₋₆ alkyl, halogen, —OH, or —OC₁₋₆ alkyl.

In another embodiment, compounds of Formula (Ic) are disclosed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereof;wherein:

A is independently N or CR_(x);

U is O, S, NR_(y), C═O, or C(R_(x))_(m);

V is O, S, N, NR_(y), C═O, or C(R_(x))_(m);

each W is independently selected from O, S, C═O, N, NR_(y) orC(R_(x))_(m);

------- is an optional double bond which allows the E ring to bepartially or fully saturated;

X is CH or C;

Y is OH or O;

R₃ is H;

n is 0, 1, or 2;

each m is independently 1, or 2;

R is H, OH, or CH₃;

R_(x) is H, C₁₋₆ alkyl, halogen, —OH, or —OC₁₋₆ alkyl; and

R_(y) is H, or C₁₋₆ alkyl.

In another embodiment, compounds of Formula (Id) are disclosed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereof;wherein:A, B, C, and D are independently N or CR_(x);

X is CH or C; Y is OH or O; R₃ is H;

n is 0, 1, or 2;

R is F; and

R_(x) is H, C₁₋₆ alkyl, halogen, —OH, or —OC₁₋₆ alkyl.

In another aspect, compounds of Formula (Ie) are disclosed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereof;wherein:

A is independently N or CR_(x);

U is O, S, NR_(y), C═O, or C(R_(x))_(m);

V is O, S, N, NR_(y), C═O, or C(R_(x))_(m);

each W is independently selected from O, S, C═O, N, NRx or C(R_(x))_(m);

------- is an optional double bond which allows the E ring to bepartially or fully saturated;

X is CH or C;

Y is OH or O;

R₃ is H;

n is 0, 1 or 2;

each m is independently 1, or 2;

R is H, OH, or CH₃;

R_(x) is H, C₁₋₆ alkyl, halogen, —OH, or —OC₁₋₆ alkyl; and

R_(y) is H, or C₁₋₆ alkyl.

In an illustrative embodiment, the compound of Formula I is

-   5-hydroxy-N-(4-methoxyphenyl)-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   5-(4-cyanophenyl)-5-hydroxy-N-(4-methoxyphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-N-(4-methylphenyl)-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(3-chlorophenyl)-5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-5-phenyl-N-[3-(trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(4-fluorophenyl)-5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-N-(3-methoxyphenyl)-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-N-(4-methoxyphenyl)-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-5-(2-methylphenyl)-N-(4-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-N-(3-methoxyphenyl)-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(3-chlorophenyl)-5-hydroxy-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-5-(2-methylphenyl)-N-[3-(trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(4-fluorophenyl)-5-hydroxy-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-5-(3-methoxyphenyl)-N-(4-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(3-chlorophenyl)-5-hydroxy-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-5-(3-methoxyphenyl)-N-[3-(trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-5-(3-methoxyphenyl)-N-(4-methoxyphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-N,    5-bis(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(2,4-difluorophenyl)-5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-[(1R)-1-(4-chlorophenyl)ethyl]-5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-N-[(2-methoxyphenyl)methyl]-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   Methyl    4-(5-hydroxy-5-(o-tolyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoate;-   5-hydroxy-N-(2-methoxy-5-methylphenyl)-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-[4-chloro-3-(trifluoromethyl)phenyl]-5-hydroxy-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-N, 5-diphenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(3-cyanophenyl)-5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-N-(2-methoxy-5-methylphenyl)-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   methyl    4-[({5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrol-2-yl}carbonyl)amino]benzoate;-   5-hydroxy-5-(3-methoxyphenyl)-N-phenyl-octahydrocyclopenta[c]pyrrloe-2-carboxamide;-   5-hydroxy-5-(2-methylphenyl)-N-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(3-cyanophenyl)-5-hydroxy-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-[4-chloro-3-(trifluoromethyl)phenyl]-5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-N-(2-methoxy-5-methylphenyl)-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-[4-chloro-3-(trifluoromethyl)phenyl]-5-hydroxy-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N,    5-bis(4-fluorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-(4-fluorophenyl)-5-hydroxy-N-(4-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-(4-fluorophenyl)-5-hydroxy-N-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-(4-fluorophenyl)-5-hydroxy-N-[3-(trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(3-chlorophenyl)-5-(4-fluorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(3-cyanophenyl)-5-(4-fluorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-(4-fluorophenyl)-5-hydroxy-N-(pyridin-3-yl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-(4-fluorophenyl)-5-hydroxy-N-(2-methoxy-5-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-[4-chloro-3-(trifluoromethyl)phenyl]-5-(4-fluorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-hydroxy-5-phenyl-N-(pyridin-3-yl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   methyl    4-({[5-hydroxy-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrol-2-yl]carbonyl}amino)benzoate;-   5-hydroxy-5-(3-methoxyphenyl)-N-(pyridin-3-yl)-octahydrocyclopenta[c]pyrrole-2-carboxamide-   N-(2,4-dimethylphenyl)-5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(2,4-dimethylphenyl)-5-hydroxy-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(2,4-dimethylphenyl)-5-hydroxy-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   methyl    4-({[5-(4-tert-butylphenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]carbonyl}amino)benzoate;-   5-(4-tert-butylphenyl)-5-hydroxy-N-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-(4-tert-butylphenyl)-N-(3-cyanophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-(4-tert-butylphenyl)-N-[4-chloro-3-(trifluoromethyl)phenyl]-5-hydroxy-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-(4-tert-butylphenyl)-5-hydroxy-N-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-(4-tert-butylphenyl)-5-hydroxy-N-[3-(trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-(4-tert-butylphenyl)-N-(3-chlorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   2-(5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-phenylethanone;-   rac-2-(2-hydroxy-2-phenylethyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol;-   2-[5-hydroxy-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrol-2-yl]-1-phenylethan-1-one;-   rac-2-(2-hydroxy-2-phenylethyl)-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrol-5-ol;-   1-(3-fluorophenyl)-2-{5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrol-2-yl)}ethan-1-one;-   1-(3-fluorophenyl)-2-[5-hydroxy-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrol-2-yl]ethan-1-one;-   rac-2-[2-(3-fluorophenyl)-2-hydroxyethyl]-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-[2-(3-fluorophenyl)-2-hydroxyethyl]-5-phenyl-octahydrocyclopenta[c]pyrrol-5-ol;-   2-{5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrol-2-yl}-1-(4-hydroxyphenyl)ethan-1-one;-   2-{5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrol-2-yl}-1-(4-methoxyphenyl)ethan-1-one;-   rac-2-[2-hydroxy-2-(4-methoxyphenyl)ethyl]-5-phenyl-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-5-phenyl-octahydrocyclopenta[c]pyrrol-5-ol;-   2-(5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-(2-hydroxypropan-2-yl)phenyl)ethanone;-   rac-2-(2-hydroxy-2-(4-(2-hydroxypropan-2-yl)phenyl)ethyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol;-   rac-5-(4-(tert-butyl)phenyl)-2-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-5-(4-tert-butylphenyl)-2-[2-(3-fluorophenyl)-2-hydroxyethyl]-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-{2-hydroxy-2-[3-(trifluoromethyl)phenyl]ethyl}-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-{2-hydroxy-2-[3-(trifluoromethyl)phenyl]ethyl}-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-5-(4-fluorophenyl)-2-{2-hydroxy-2-[3-(trifluoromethyl)phenyl]ethyl}-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]-5-(4-fluorophenyl)-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-(1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-5-(3-methoxyphenyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-(4-fluorobenzyl)-5-(4-fluorophenyl)octahydrocyclopenta[c]pyrrol-5-ol;-   5-(4-fluorophenyl)-2-(pyridin-2-yl)-octahydrocyclopenta[c]pyrrol-5-ol;-   5-(4-fluorophenyl)-2-[6-(trifluoromethyl)pyridin-2-yl]-octahydrocyclopenta[c]pyrrol-5-ol;-   5-(2-methylphenyl)-2-(pyridin-2-yl)-octahydrocyclopenta[c]pyrrol-5-ol;-   5-phenyl-2-[6-(trifluoromethyl)pyridin-2-yl]-octahydrocyclopenta[c]pyrrol-5-ol;-   5-(2-methylphenyl)-2-[6-(trifluoromethyl)pyridin-2-yl]-octahydrocyclopenta[c]pyrrol-5-ol;-   2-(6-methylpyridin-2-yl)-5-phenyl-octahydrocyclopenta[c]pyrrol-5-ol;-   5-(2-methylphenyl)-2-(6-methylpyridin-2-yl)-octahydrocyclopenta[c]pyrrol-5-ol;-   5-(4-fluorophenyl)-2-(6-methylpyridin-2-yl)-octahydrocyclopenta[c]pyrrol-5-ol;-   5-(4-tert-butylphenyl)-2-(pyridin-2-yl)-octahydrocyclopenta[c]pyrrol-5-ol;-   5-(4-tert-butylphenyl)-2-(6-methylpyridin-2-yl)-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-(5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(11H)-yl)-1-(4-hydroxyphenyl)propan-1-one;-   rac-2-(1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-[5-(4-fluorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)propan-1-one;-   rac-2-[5-(4-tert-butylphenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)propan-1-one;-   rac-2-[5-hydroxy-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)propan-1-one;-   rac-2-[1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl]-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-5-(4-tert-butylphenyl)-2-[1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl]-octahydrocyclopenta[c]pyrrol-5-ol;-   (5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(4-hydroxyphenyl)methanone;-   3-(5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one;-   2-(3-hydroxy-3-(4-hydroxyphenyl)propyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol;-   2N-(4-methoxyphenyl)-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   N-(4-hydroxyphenyl)-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(4-fluorophenyl)-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N,5-diphenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   methyl    4-[({5-phenyl-octahydrocyclopenta[c]pyrrol-2-yl}carbonyl)amino]benzoate;-   N-(3-methoxyphenyl)-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-phenyl-N-[3-(trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyrrloe-2-carboxamide;-   N-(3-chlorophenyl)-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(3-cyanophenyl)-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-[4-chloro-3-(trifluoromethyl)phenyl]-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(2-methoxy-5-methylphenyl)-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-(2,4-dimethylphenyl)-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   5-phenyl-N-(pyridin-3-yl)-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-[(2-methoxyphenyl)methyl]-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   N-[(1R)-1-(4-chlorophenyl)ethyl]-5-phenyl-octahydrocyclopenta[c]pyrrole-2-carboxamide;-   1-(4-hydroxyphenyl)-2-(5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone;-   4-(1-hydroxy-2-(5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol;-   rac-2-(5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3-(trifluoromethyl)phenyl)ethanol;-   rac-1-(3-methoxyphenyl)-2-{5-phenyl-octahydrocyclopenta[c]pyrrol-2-yl}ethan-1-ol;-   (3    aR,5r,6aS)-5-benzyl-N-(3-chlorophenyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   (3aR,5r,6aS)-5-benzyl-5-hydroxy-N-(3-methoxyphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   (3aR,5r,6aS)-5-benzyl-N-(4-chloro-3-(trifluoromethyl)phenyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   (3 aR, 5r,    6aS)-5-benzyl-N-(2,4-dimethylphenyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   (3 aR,5r,    6aS)-5-benzyl-5-hydroxy-N-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   (3aR,5r,6aS)-5-benzyl-N-(3-cyanophenyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   (3aR,5r,6aS)-5-benzyl-5-hydroxy-N-(2-methoxy-5-methylphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   (3aR,5r,    6aS)-5-benzyl-5-hydroxy-N-(p-tolyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide-   (3aR,5r,6aS)-5-benzyl-5-hydroxy-N-(4-methoxyphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   (3aR,5r,6aS)-5-benzyl-5-hydroxy-N-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   (3aR,5r,6aS)-5-benzyl-5-hydroxy-N-(2-methoxyphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   (3aR,5r,6aS)-5-benzyl-5-hydroxy-N-(m-tolyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-(3 aR,    5r,6aS)-5-benzyl-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-methoxyphenyl)ethanone;-   3-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one;-   2-((3 aR,    5r,6aS)-5-(4-fluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-(3 aR, 5r,    6aS)-5-(4-fluorobenzyl)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   (3aR,5R,6aS)-5-benzyl-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   (3 aR, 5    S,6aS)-5-benzyl-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-(2-hydroxypropan-2-yl)phenyl)ethanone;-   rac-(3    aR,5r,6aS)-5-benzyl-2-(2-hydroxy-2-(4-(2-hydroxypropan-2-yl)phenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   N-(4-(2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)phenyl)acetamide;-   (3aR,5R,6aS)-5-benzyl-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   (3 aR, 5    S,6aS)-5-benzyl-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-(3    aR,5r,6aS)-5-benzyl-2-(2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   1-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-(4-hydroxyphenyl)propan-2-one;-   N-(4-(2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)phenyl)methanesulfonamide;-   5-(2-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)indolin-2-one;-   6-(2-((3 aR,    S5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)-3,4-dihydroquinolin-2(1H)-one;-   rac-N-(4-(2-((3 aR,    5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenyl)acetamide;-   rac-N-(4-(2-((3 aR,    5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenyl)methanesulfonamide;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3-fluoro-4-hydroxyphenyl)ethanone;-   rac-5-(2-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)indolin-2-one;-   rac-6-(2-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one;-   rac-6-(2-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)benzo[d]oxazol-2(3H)-one;-   2-((3 aR,    5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(6-chloropyridin-3-yl)ethanone;-   (3aR,5    S,6aS)-5-benzyl-2-((S)-2-(3-fluoro-4-hydroxyphenyl)-2-hydroxyethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   6-(2-((3 aR,    5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)pyridazin-3    (2H)-one;-   rac-6-(2-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridazin-3    (2H)-one;-   2-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3,5-difluoro-4-hydroxyphenyl)ethanone;-   rac-(3    aR,5r,6aS)-5-benzyl-2-(2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(6-methoxypyridin-3-yl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-(benzyloxy)pyrazin-2-yl)ethanone;-   rac-(3 aR, 5r,    6aS)-5-benzyl-2-(2-(5-(benzyloxy)pyrazin-2-yl)-2-hydroxyethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   (3aR,5    S,6aS)-5-benzyl-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   (3aR,5R,6aS)-5-benzyl-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3 aR,    5r,6aS)-5-(4-fluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   2-[(3aR,5R,6aS)-5-benzyl-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-(1H-1,2,3-benzotriazol-5-yl)ethan-1-one;-   rac-(3 aR,    5r,6aS)-5-(4-fluorobenzyl)-2-(2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   1-(3-fluoro-4-hydroxyphenyl)-2-((3 aR, 5r,    6aS)-5-(4-fluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone;-   2-((3 aR,    5r,6aS)-5-benzyl-5-methoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3-fluoro-4-hydroxyphenyl)ethanone;-   rac-(3 aR, 5r,    6aS)-2-(2-(3-fluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(4-fluorobenzyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3-fluoro-4-(2-(3-fluoro-4-hydroxyphenyl)-2-oxoethoxy)phenyl)ethanone;-   2-(2-fluoro-4-(2-((3 aR,    5r,6aS)-5-(4-fluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)phenoxy)-1-(3-fluoro-4-hydroxyphenyl)ethanone;-   2-((3    aR,5r,6aS)-5-benzyl-5-methoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-4-(2-((3 aR,    5r,6aS)-5-benzyl-5-methoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)-2-fluorophenol;-   rac-4-(2-((3 aR,    5r,6aS)-5-benzyl-5-methoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol;-   rac-6-(2-((3 aR,    5r,6aS)-5-benzyl-5-methoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol;-   2-[(3    aR,5R,6aS)-5-benzyl-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-(6-hydroxypyridin-3-yl)ethan-1-one;-   2-((3 aR,    5r,6aS)-5-hydroxy-5-(4-methylbenzyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   (3aR,5R,6aS)-5-benzyl-2-((R)-2-(3-fluoro-4-hydroxyphenyl)-2-hydroxyethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   (3aR,5    S,6aS)-5-benzyl-2-((S)-2-(3-fluoro-4-hydroxyphenyl)-2-hydroxyethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-5-{2-[(3    aR,5R,6aS)-5-benzyl-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl}pyridin-2-ol;-   rac-(3 aR,    5R,6aS)-2-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-5-[(4-methylphenyl)methyl]-octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3 aR,    5r,6aS)-5-hydroxy-5-(2-methylbenzyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   2-[(3 aR,    5R,6aS)-5-hydroxy-5-[(4-methoxyphenyl)methyl]-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethan-1-one;-   rac-(3 aR, 5r,    6aS)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-5-(2-methylbenzyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-(3    aR,5R,6aS)-2-[2-(1H-1,2,3-benzotriazol-5-yl)-2-hydroxyethyl]-5-benzyl-octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyrazin-2-yl)ethanone;-   rac-(3 aR, 5r,    6aS)-5-benzyl-2-(2-hydroxy-2-(5-hydroxypyrazin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-(3 aR, 5r,    6aS)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-5-(4-methoxybenzyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(6-fluoro-5-hydroxypyridin-2-yl)ethanone;-   rac-(3 aR, 5r,    6aS)-5-benzyl-2-(2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-[(3 aR,    5R,6aS)-5-hydroxy-5-[(4-methoxyphenyl)methyl]-octahydrocyclopenta[c]pyrrol-2-yl]-1-(5-hydroxypyridin-2-yl)ethan-1-one;-   2-((3 aR,    5r,6aS)-5-hydroxy-5-(3-methoxybenzyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   2-((3 aR,    5r,6aS)-5-hydroxy-5-(3-methoxybenzyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-(3 aR,    5r,6aS)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-5-(3-methoxybenzyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-((3 aR,    5r,6aS)-2-(2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-(3-methoxybenzyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3 aR,    5r,6aS)-5-benzyl-5-methoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(6-fluoro-5-hydroxypyridin-2-yl)ethanone;-   rac-6-(2-((3 aR,    5r,6aS)-5-benzyl-5-methoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)-2-fluoropyridin-3-ol;-   rac-6-{2-[(3aR,5R,6aS)-5-hydroxy-5-[(4-methoxyphenyl)methyl]-octahydrocyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl}pyridin-3-ol;-   1-(6-fluoro-5-hydroxypyridin-2-yl)-2-((3    aR,5r,6aS)-5-hydroxy-5-(3-methoxybenzyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone;-   rac-(3aR,5r,6aS)-2-(2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-(3-methoxybenzyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-[(3 aR,    5R,6aS)-5-benzyl-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-(5-hydroxypyrimidin-2-yl)ethan-1-one;-   rac-2-{2-[(3    aR,5R,6aS)-5-benzyl-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl}pyrimidin-5-ol;-   rac-(3 aR, 5r,    6aS)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-5-(thiophen-2-ylmethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-[(3    aR,5R,6aS)-5-(cyclohexylmethyl)-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethan-1-one;-   2-[(3    aR,5R,6aS)-5-(cyclohexylmethyl)-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-(5-hydroxypyridin-2-yl)ethan-1-one;-   2-((3    aR,5r,6aS)-5-(cyclopropylmethyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   rac-6-{2-[(3    aR,5R,6aS)-5-[(3,5-dimethylphenyl)methyl]-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl}pyridin-3-ol-3-ol;-   rac-(3 aR,    5R,6aS)-5-(cyclohexylmethyl)-2-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3    aR,5r,6aS)-5-(cyclopropylmethyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-(3 aR, 5r,    6aS)-5-(cyclopropylmethyl)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-[(3    aR,5R,6aS)-5-[(3,5-dimethylphenyl)methyl]-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethan-1-one;-   rac-(3aR,5R,6aS)-5-[(3,5-dimethylphenyl)methyl]-2-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-octahydrocyclopenta[c]pyrrol-5-ol;-   rac-6-{2-[(3 aR,    S5R,6aS)-5-(cyclohexylmethyl)-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl}pyridin-3-ol;-   rac-2-(2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-(thiophen-2-ylmethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-[(3 aR, 5R,    6aS)-5-hydroxy-5-{[4-(trifluoromethyl)phenyl]methyl})-octahydrocyclopenta[c]pyrrol-2-yl]-1-(5-hydroxypyridin-2-yl)ethan-1-one;-   rac-6-{2-[(3aR,5R,6aS)-5-hydroxy-5-{[4-(trifluoromethyl)phenyl]methyl})-octahydrocyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl}pyridin-3-ol;-   2-((3aR,5r,6aS)-5-(4-chlorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   2-[(3 aR, 5R,    6aS)-5-hydroxy-5-{[4-(trifluoromethyl)phenyl]methyl})-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethan-1-one;-   1-(3-fluoro-4-hydroxyphenyl)-2-(5-hydroxy-5-(thiophen-2-ylmethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone;-   2-(5-(2-fluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   rac-2-(2-(3-fluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(thiophen-2-ylmethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-(3    aR,5r,6aS)-5-(4-chlorobenzyl)-2-(2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-(3aR,5R,6aS)-2-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-5-{[4-(trifluoromethyl)phenyl]methyl}-octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3 aR,    5r,6aS)-5-(2-fluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   2-((3    aR,5r,6aS)-5-hydroxy-5-(pyridin-4-ylmethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-(3 aR, 5r,    6aS)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-5-(pyridin-4-ylmethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-5-(2-fluorobenzyl)-2-(2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-olyl)ethanone;-   rac-(3 aR, 5r,    6aS)-5-(2-fluorobenzyl)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3aR,5r,6aS)-5-(2,4-difluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   2-((3    aR,5r,6aS)-5-hydroxy-5-(pyridin-2-ylmethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-(3 aR, 5r,    6aS)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-5-(pyridin-2-ylmethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-(3 aR, 5r,    6aS)-5-(2,4-difluorobenzyl)-2-(2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol-   2-((3aR,5r,6aS)-5-(2-chlorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   N-(6-(2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)pyridin-3-yl)methanesulfonamide    rac-N-(6-(2-((3 aR,    5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-yl)methanesulfonamide;-   2-[(3 aR,    5R,6aS)-5-[(2,6-difluorophenyl)methyl)methyl]-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-(5-hydroxypyridin-2-yl)ethan-1-one;-   2-(5-(2,4-difluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   2-((3aR,5r,6aS)-5-(3,4-difluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   rac-6-{2-[(3    aR,5R,6aS)-5-[(2,6-difluorophenyl)methyl]-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl}pyridin-3-ol-   2-[(3 aR,    5R,6aS)-5-[(2,6-difluorophenyl)methyl)methyl]-5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethan-1-one;-   2-((3    aR,5r,6aS)-5-(4-fluoro-2-methylbenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   rac-(3 aR, 5r,    6aS)-5-(4-fluoro-2-methylbenzyl)-2-(2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3    aR,6aS)-5-(2-fluoropyridin-3-yl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   rac-5-(2,4-difluorobenzyl)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-(3 aR,    5r,6aS)-5-(2-chlorobenzyl)-2-(2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3    aR,5r,6aS)-5-(2,3-difluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   rac-(3    aR,5r,6aS)-5-(2,3-difluorobenzyl)-2-(2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol-   2-((3    aR,5r,6aS)-5-(2,3-difluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   2-((3    aR,5r,6aS)-5-(4-fluoro-2-methylbenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-(3    aR,6aS)-5-(2-fluoropyridin-3-yl)-2-(2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3aR,5r,6aS)-5-(3,4-difluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-(3 aR, 5r,    6aS)-5-(3,4-difluorobenzyl)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-(3 aR, 5r,    6aS)-5-(4-fluoro-2-methylbenzyl)-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   (3 aR, 5    S,6aS)-5-(4-fluorobenzyl)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   (3aR,5R,6aS)-5-(4-fluorobenzyl)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4′-hydroxy-[1,1′-biphenyl]-4-yl)ethanone;-   1-([1,1′-biphenyl]-4-yl)-2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4′-methoxy-[1,1′-biphenyl]-4-yl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(2′-methyl-[1,1′-biphenyl]-4-yl)ethanone;-   2-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3′-fluoro-[1,1′-biphenyl]-4-yl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4′-fluoro-[1,1′-biphenyl]-4-yl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4′-methoxy-[1,1′-biphenyl]-3-yl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3′-methyl-[1,1′-biphenyl]-4-yl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethanone;-   2-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-(pyridin-2-yl)phenyl)ethanone;-   2-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-(pyridin-3-yl)phenyl)ethanone;-   1-([1,1′-biphenyl]-3-yl)-2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone;-   2-[5-hydroxy-5-(2-phenylethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-phenylphenyl)ethan-1-one;-   1-[4-(3-fluorophenyl)phenyl]-2-[5-hydroxy-5-(2-phenylethyl)-octahydrocyclopenta[c]pyrrol-2-yl]ethan-1-one;-   2-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3′-fluoro-[1,1′-biphenyl]-3-yl)ethanone;-   2-((3    aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3-(pyridin-3-yl)phenyl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3′-methoxy-[1,1′-biphenyl]-3-yl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4′-fluoro-[1,1′-biphenyl]-3-yl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4′-hydroxy-[1,1′-biphenyl]-3-yl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3′-methyl-[1,1′-biphenyl]-3-yl)ethanone;-   2-[5-hydroxy-5-(2-phenylethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-1-[4-(3-methylphenyl)phenyl]ethan-1-one;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(2′-methyl-[1,1′-biphenyl]-3-yl)ethanone;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-(2-methoxypyrimidin-5-yl)phenyl)ethanone;-   rac-(3 aR,    5R,6aS)-5-benzyl-2-[2-hydroxy-2-(4-hydroxyphenyl)propyl]-octahydrocyclopenta[c]pyrrol-5-ol;-   deuterated rac-(3    aR,6aS)-5-benzyl-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   N-(5-(2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)pyridin-2-yl)acetamide;-   rac-N-(5-(2-((3 aR,    5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-2-yl)acetamide;-   tert-butyl    (5-(2-(5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)pyridin-2-yl)carbamate;-   N-(5-(2-(5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)pyridin-2-yl)pivalamide;-   rac-N-(5-(2-(5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-2-yl)pivalamide;-   rac-(3 aR, 5r,    6aS)-5-benzyl-2-(2-(2,4-dichlorophenyl)-2-hydroxyethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-(3aR,5r,6aS)-5-benzyl-2-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-(3 aR, 5r,    6aS)-5-benzyl-2-(2-(4-fluorophenyl)-2-hydroxyethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   (3aR,5R,6aS)-5-benzyl-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   (3 aR, 5    S,6aS)-5-benzyl-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one;-   (3    aR,6aS)-5-benzyl-N-(3-methoxyphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide;-   2-((3aR,6aS)-5-benzylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-2-((3aR,6aS)-5-benzylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one;-   2-{5-benzyl-octahydrocyclopenta[c]pyrrol-2-yl}-1-(5-hydroxypyridin-2-yl)ethan-1-one;-   rac-6-(2-{5-benzyl-octahydrocyclopenta[c]pyrrol-2-yl}-1-hydroxyethyl)pyridin-3-ol;-   2-{5-benzyl-octahydrocyclopenta[c]pyrrol-2-yl}-1-(3-fluoro-4-hydroxyphenyl)ethan-1-one;-   rac-4-(2-((3aR,6aS)-5-benzylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol;-   rac-4-{2-[(3 aR,5    S,6aS)-5-benzyl-octahydrocyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl}-2-fluorophenol;-   rac-4-{2-[(3aR,5R,6aS)-5-benzyl-octahydrocyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl}-2-fluorophenol;-   2-[(3 aR, 5    S,6aS)-5-benzyl-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethan-1-onefluorophenol;-   rac-4-{2-[(3 aR,5    S,6aS)-5-benzyl-octahydrocyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl}phenol;-   2-[(3 aR, 5R,    6aS)-5-benzyl-octahydrocyclopenta[c]pyrrol-2-yl]-1-(4-hydroxyphenyl)ethan-1-one;-   rac-4-{2-[(3    aR,5R,6aS)-5-benzyl-octahydrocyclopenta[c]pyrrol-2-yl]-1-hydroxyethyl}phenol;-   2-[(3 aR,5    S,6aS)-5-benzyl-octahydrocyclopenta[c]pyrrol-2-yl]-1-(3-fluoro-4-hydroxyphenyl)ethan-1-one;-   2-[(3aR,5R,6aS)-5-benzyl-octahydrocyclopenta[c]pyrrol-2-yl]-1-(3-fluoro-4-hydroxyphenyl)ethan-1-one;-   rac-2-((3aR,6aS)-5-benzylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3-(trifluoromethyl)phenyl)ethanol;-   2-((3 aR,5    s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-4-(2-((3 aR,5    s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol;-   4-(2-((3 aR,5    s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol;-   rac-4-(2-((3aR,5r,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol;-   4-((R)-2-((3 aR, 5    S,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol;-   4-((S)-2-((3    aR,5R,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol;-   rac-4-(2-((3 aR,5    s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)-2-fluorophenol;-   rac-2-((3aR,5    s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one;-   rac-4-(2-((3 aR,5    s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxypropyl)phenol;-   rac-2-(5-hydroxy-5-phenethylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one;-   rac-2-(1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-5-phenethyloctahydrocyclopenta[c]pyrrol-5-ol;-   rac-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-5-phenethyloctahydrocyclopenta[c]pyrrol-5-ol;-   rac-1-(4-hydroxyphenyl)-2-[(5R)-5-(2-phenylethyl)-octahydrocyclopenta[c]pyrrol-2-yl]propan-1-one;-   1-(4-hydroxyphenyl)-2-(5-phenethylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone;-   1-(4-hydroxyphenyl)-2-((3 aR,    5r,6aS)-5-phenethylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone;    or-   1-(4-hydroxyphenyl)-2-((3 aR,    5r,6aS)-5-phenethylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)propan-1-one.

In another aspect, compounds of Formula II are described:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereofwherein R₁, L₁, Y, Y′, L₂, and R₂ are as described above for Formula II.

In another embodiment, compounds of Formula (IIa) are disclosed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereof;wherein:

A is independently N or CR_(x);

U is O, S, NR_(y), C═O, or C(R_(x))_(m);

V is O, S, N, NR_(y), C═O, or C(R_(x))_(m);

each W is independently selected from O, S, C═O, N, NR_(y) orC(R_(x))_(m);

------- is an optional double bond which allows the E ring to bepartially or fully saturated;

X is CH or C;

Y is OH or O;

R₃ is H;

each m is independently 1, or 2;

R is H, OH, or CH₃;

R_(x) is H, C₁₋₆ alkyl, halogen, —OH, or —OC₁₋₆ alkyl; and

R_(y) is H, or C₁₋₆ alkyl.

In another embodiment, compounds of Formula (IIb) are disclosed:

wherein:

A, B, C, and D are independently N or CR_(x);

X is CH or C;

Y is OH or O;

R₃ is H; and

R_(x) is H, C₁₋₆ alkyl, halogen, —OH, or —OC₁₋₆ alkyl.

In another embodiment of Formula II L₁ is —C(O)—, —C(O)—C₁-C₃alkylenyl-,—S(O)₂—, —S(O)₂NH—, —CONH—, —CON(R₁₀)—, or a bond.

In another embodiment of the compounds of Formula II, L₁ is C₁-C₂ alkylor C₁-C₂ branched alkyl substituted with OH.

In another embodiment of the compounds of Formula II, L₁ is—C(O)—C₁-C₃alkylenyl-.

In yet another embodiment of the compounds of Formula II, L₂ is a bond,(CH₂)_(n) or (CHR₁₁)_(n) and n is 1.

In another embodiment of the compounds of Formula II, Y and Y′ are H.

In another embodiment of the compounds of Formula II, Y and Y′ aremethyl.

In other embodiments, illustrative compounds of Formula II include:

-   2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone;-   rac-4-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol;-   2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;-   rac-6-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol;-   2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(3-fluoro-4-hydroxyphenyl)ethanone;    or-   rac-4-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-hydroxyethyl)-2-fluorophenol.

In another aspect, compounds of Formula III are described:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or stereoisomers thereofwherein R₁, L₁, X, L₂, and R₂ are as described above for Formula III:

In another embodiment, compounds of Formula (IIIa) are disclosed:

wherein:

X is CH or C;

Y is OH or O; Other embodiments of this invention relate to compounds ofFormula III where L₁ is straight or branched C₁-C₅ alkyl substitutedwith OH.

In other embodiments of the compounds of Formula III, L₁ is—C(O)—C₁-C₃alkylenyl-.

In other embodiments of the compounds of Formula III, L₁ is —C(O)O—.

In other embodiments of the compounds of Formula III, L₂ is (CH₂)_(n) or(CHR₁₁)_(n) and n is 0.

In yet other embodiments of the compounds of Formula III, L₂ is(CH₂)_(n) or (CHR₁₁)_(n) and n is 1.

In other embodiments of the compounds of Formula III, L₂ is (CH₂)_(n) or(CHR₁₁)_(n) and n is 2.

In another embodiment of the compounds of Formula III, R₂ is phenyl. Inanother embodiment of the compounds of Formula III, R₂ is phenylsubstituted with OH, OR₁₀, or CN.

In another embodiment of the compounds of Formula III, R₁ is C₁-C₆ alkylor cycloalkyl.

In another embodiment of the compounds of Formula III, R₁ is C₁-C₆alkyl.

In another embodiment of the compounds of Formula III, R₁ is arylsubstituted with OH.

In another embodiment of the compounds of Formula III, R₁ is phenylsubstituted with OH.

In another embodiment of the compounds of Formula III, R₁ is heteroarylsubstituted with OH.

In other embodiments of the invention, suitable compounds of Formula IIIinclude:

-   2-(6-benzyl-6-hydroxy-2-azaspiro[3.3]heptan-2-yl)-1-(4-hydroxyphenyl)ethanone;    or-   rac-6-benzyl-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-2-azaspiro[3.3]heptan-6-ol.

In an embodiment, the present disclosure includes Formula I, Formula IIand Formula III compounds where any hydrogen atom may be replaced with adeuterium atom.

In another embodiment, tautomers of Formula I, Formula II, and FormulaIII are also described.

Methods of Using the Disclosed Compounds

In an embodiment, the present disclosure pertains to compounds thatselectively modulate the activity of NMDA receptors that contain an NR2Bsubunit, which encompasses receptors containing two NR2B subunits or oneNR2B subunit in combination with one other NR2 subunit (i.e., NR2A/NR2B,NR2B/NR2C, or NR2B/NR2D receptors). The present disclosure also relatesto the therapeutic uses of such compounds.

One therapeutic use of a compound of the present invention thatmodulates the activity of NR2B-containing NMDA receptors is to treatpatients suffering from Major Depressive Disorder (MDD, or depression).Depression is the prolonged experience of sadness, hopelessness, orworthlessness to a degree that significantly impairs quality of life andthe ability to function Major Depressive Disorder is now commonlytreated with Selective Serotonin Reuptake Inhibitors (SSRIs) such asProzac, Zoloft and newer variants, but these agents are of limitedeffectiveness. Of additional concern is that even when these drugs areeffective, the onset of action is may be delayed 4-6 weeks or more,during which time patients are at increased risk of suicide.Consequently, the Food and Drug Administration has inserted a black-boxwarning on all antidepressants concerning suicide risk. There is a needfor new agents with greater antidepressant efficacy and faster onset ofaction.

Another therapeutic use for compounds of the present invention is in thetreatment of schizophrenia. Schizophrenia is a debilitating mentaldisorder encompassing three symptom domains: positive (hallucination,delusions), negative (withdrawal), and cognitive (pervasive reduction incognitive ability). Schizophrenia typically strikes in early adulthoodwith the emergence of positive symptoms; however, it is the chroniccognitive deficits that prevent patients from resuming normal activitiesafter the initial onset of symptoms and largely accounts for a lifetimedisability.

Given the fundamental role of NR2B containing NMDA receptors in brainfunction (vide supra), there are many other therapeutic uses forcompounds of the present invention that modulate the activity ofNR2B-continaing NMDA receptors. Compounds of the present invention mayimprove cognitive function in individuals suffering from cognitivedeficits in addition to schizoprhenia, including but not limited tothose suffering from Alzheimer's disease. Such compounds may also beused in the treatment of post-traumatic stress syndrome. Compounds ofthe present invention may be used to treat individuals suffering fromneurological dysfunction, including but not limited to those sufferingfrom Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, multiple sclerosis, and seizure disorders. Compounds of thepresent invention may be used to treat individuals suffering fromemotional disorders in addition to depression, including but not limitedto those suffering from bipolar disorder, obsessive-compulsive disorderand other anxiety disorders. Compounds of the present invention may beused to treat individuals that experience dysfunction caused by abnormalbrain development, including but not limited to those suffering fromautism and autism spectrum disorders, Fragile X syndrome, tuberoussclerosis, Down's syndrome and other forms of mental retardation. Suchcompounds may also be used to treat abnormal brain function that resultsfrom infections of the central nervous system, exposure to toxic agentsor other xenobiotics or naturally occurring toxins.

The disclosed compound can be administered in effective amounts to treator prevent a disorder and/or prevent the development thereof insubjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, all using forms well known to thoseskilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algiic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoylresidues. Furthermore, the Disclosed compounds can be coupled to a classof biodegradable polymers useful in achieving controlled release of adrug, for example, polylactic acid, polyepsilon caprolactone,polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels. In one embodiment, Disclosed compoundsare not covalently bound to a polymer, e.g., a polycarboxylic acidpolymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

In many examples and intermediates, there is a plane of symmetry presentin the molecules presented resulting in an achiral, meso compound. Thereis, however, relative stereochemistry between groups which is described.For example,2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-methoxyphenyl)ethanonehas a core structure that is designated with absolute configurationdesignations. This nomenclature is used to describe the relativeconfigurations of the benzyl group with respect to the bridgeheadhydrogens. In this example, the benzyl substituent is exo with respectto the larger pyrrolidine ring of the bicyclic system as drawn. It isunderstood that when multiple stereoisomers may exist, all are includedwithin the scope of the invention. In cases where any substituent alsocontains a stereogenic center, the compound becomes chiral and we usethe designator “rac” to denote the synthesis of racemic mixtures ofthese examples. It is understood that the single enantiomers can beseparated from this mixture and are included within the scope of theinvention.

Example 1—Preparation of5-hydroxy-N-(4-methoxyphenyl)-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

Step-1: Preparation of Benzyl Allylcarbamate

To a stirred suspension of K₂CO₃ (121 g, 2.0 eq, 876.4 mmol) in ethylacetate (600 mL) and water (600 mL) was added prop-2-en-1-amine (20.0 g,350.5 mmol) at room temperature. The reaction mixture was cooled to 0°C. Benzyl carbonochloridate (71.76 g, 420.6 mmol) was added drop wise tothe above reaction mixture at 0° C. The reaction mixture was allowed tocool to room temperature and stirred for 16 h. After completion of thereaction (monitored by TLC), the organic layer was washed with sodiumbicarbonate solution (200 mL×2), water (200 mL×2), brine (100 mL), driedover sodium sulfate, filtered and evaporated to afford the crudeproduct, which was purified by silica gel column chromatography (10%ethyl acetate/hexane) to obtain the title compound benzyl allylcarbamate(65 g, 97% yield) as colorless liquid. Calculated (M+H): 192.09; Found(M+1): 192.2.

Step-2: Preparation of benzyl allyl(prop-2-yn-1-yl)carbamate

To a stirred suspension of sodium hydride (95%) (19.57 g, 815.8 mmol) indry tetrahydrofuran (800 mL) was added benzyl allylcarbamate (78 g,177.0 mmol) slowly at 0° C., the reaction mixture was allowed to warm toroom temperature and stirred for 30 min. After 30 min, the reactionmixture was cooled to 0° C., propargyl bromide solution (80 wt. % intoluene) (159 mL, 0.62 mmol) was added slowly to the reaction mixture,and allowed to warm to room temperature and stirred for 3 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasquenched with cold water, extracted with ethyl acetate (500 mL×3). Thecombined organic layer was washed with water (200 mL×2), brine (200 mL),dried over sodium sulfate, filtered and concentrated under vacuum toafford the crude product, which was purified by silica gel columnchromatography (8% ethyl acetate/hexane) to obtain the title compoundbenzyl allyl(prop-2-yn-1-yl)carbamate (74 g, 79% yield) as a yellowliquid. Calculated (M+H): 230.11; Found (M+1): 230.2.

Step-3: Preparation of benzyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a stirred solution of benzyl allyl(prop-2-yn-1-yl)carbamate (40 g,174.4 mmol) in a mixture of water and dimethoxyethane (65 mL: 400 mL)was added dicobalt octacarbonyl [moistened with hexane (hexane 1-10%),≥90% (Co)] (72 g, 191.9 mmol) at 0° C. The reaction mixture was allowedto warm to room temperature slowly and heated to 100° C. and stirred for3 h. After completion of reaction (monitored by TLC), the reactionmixture was concentrated to afford crude product which was purified bysilica gel column chromatography (50% ethylacetate/hexane) to obtain thetitle compound benzyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (33 g, 73% yield)as a brown solid. Calculated (M+H): 260.12; Found (M+H): 260.2.

Step-4: Preparation of benzyl5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a stirred solution of bromobenzene (6.0 g, 38.21 mmol) in drytetrahydrofuran (120 mL) was added sec-BuLi (1.3 M in hexane) (43.5 mL,57.32 mmol) at −78° C. slowly under N₂. The reaction mixture was stirredfor 15 min at −78° C., then allowed to warm to −40° C. and stirred for30 min. The reaction mixture was cooled to −78° C., a solution of benzyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (6.9 g, 26.75 mmol)in dry tetrahydrofuran was added drop wise at −78° C., stirred for 1 hat −78° C. and gradually warmed to room temperature in 2 h. Aftercompletion of reaction (monitored by TLC), quenched with saturatedsolution of ammonium chloride (100 mL) and the mixture extracted withethyl acetate (250 mL×3). The combined organic layer was concentrated toafford the crude product which was purified by silica gel columnchromatography (35% ethylacetate/hexane) to obtain the title compoundbenzyl 5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(2.95 g, 33% yield) as a pale yellow solid. Calculated (M+H): 338.17;Found [(M+H)—H2O]: 320.2.

Step-5: Preparation of 5-phenyloctahydrocyclopenta[c]pyrrol-5-ol

To a stirred solution of benzyl5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (7.2g, 0.02 mmol) in ethanol (100 mL), was added 10% Pd/C (1.4 g) under N₂atmosphere. The reaction subjected to hydrogenation in balloon andstirred for 6 h. After completion of reaction (monitored by TLC), thereaction mixture was filtered through celite bed, washed with methanol.The filtrate was concentrated under vacuum to obtain the title compound5-phenyloctahydrocyclopenta[c]pyrrol-5-ol (4.0 g (crude), 97% yield) asa pale yellow liquid. Calculated (M+H): 204.13; Found (M+H): 204.0.

Step-6: Preparation of5-hydroxy-N-(4-methoxyphenyl)-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

To a stirred solution of 5-phenyloctahydrocyclopenta[c]pyrrol-5-ol (0.05g, 0.25 mmol) in dichloromethane (5 mL), was added diisopropylethylamine (0.08 mL, 0.49 mmol) and 1-isocyanato-4-methoxybenzene (0.04g, 0.27 mmol) at 0° C., the reaction mixture was allowed to warm to roomtemperature and stirred for 8 h. After completion of reaction (monitoredby TLC) the reaction mixture was quenched with saturated sodiumbicarbonate solution (10 mL) and extracted with dichloromethane (25mL×2). The combined organic layer was washed with water (10 mL), brine(10 mL), dried over anhydrous sodium sulfate and concentrated underreduced pressure to afford the crude compound which was purified bysilica gel column chromatography (3% methanol/dichloromethane) to obtainthe title compound5-hydroxy-N-(4-methoxyphenyl)-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide(0.056 g, 69% yield) as a white solid. Calculated (M+H): 353.18; Found(M+H): 353.4.

Example 2—Preparation of (3aR,6aS)-benzyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Step-1: Preparation of 2,3,3a,4,7,7a-hexahydro-1H-isoindole

Lithium aluminium hydride (197 g, 5.19 mol) powder was added totetrahydrofuran (6500 mL) at 0° C. and stirred for 30 minutes. Then asolution of 3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (314 g,2.077 mol) in tetrahydrofuran (700 mL) was added slowly drop wise to theabove suspension over a period of 2 h. The reaction mass was thenallowed to warm up to room temperature and stirred at 60° C. for 16 h.After completion of reaction (monitored by TLC), reaction mass wascooled to 0° C. and quenched with water (200 mL) followed by theaddition of 15% aqueous potassium hydroxide solution. The resultingsuspension was filtered through celite and the bed was thoroughly washedwith dichloromethane (2000 mL). The combined filtrate was concentratedunder vacuum to get the title compound2,3,3a,4,7,7a-hexahydro-1H-isoindole (270 g, crude) as a brownish liquidwhich was used for next step without further purification. CalculatedM+H: 124.10; Found M+H: 124.12.

Step-2: Preparation of benzyl1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate

To a stirred solution of 2,3,3a,4,7,7a-hexahydro-1H-isoindole (270 g,2.19 mol) in dry dichloromethane (5.5 liter) at 0° C. were addedtriethylamine (607 mL, 4.35 mol) and benzyl chloroformate (311.6 mL,2.19 mol) under inert atmosphere. The reaction mass was warmed to roomtemperature and stirred for 16 h. After completion of reaction(monitored by TLC), reaction mass was diluted with dichloromethane (2000mL) followed by addition of water (5000 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate and evaporated undervacuum to get crude product which was purified by column chromatographyusing 100-200 mesh silica gel and 5% ethyl acetate/hexane as eluent toafford the title compound benzyl1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate (303 g, 53.7%) as abrownish liquid. Calculated M+H: 258.14; Found M+H: 258.18.

Step-3: Preparation of2,2′-(1-((benzyloxy)carbonyl)pyrrolidine-3,4-diyl)diacetic acid

To a stirred solution of benzyl1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate (303 g, 1.177 mol) inpentane (1200 mL) was added a solution of potassium permanganate (558 g,3.53 mol) and tetrabutyl ammonium bromide (56.9 g, 0.177 mol) in water(7500 mL) at 0° C. and the reaction mixture was warmed to roomtemperature. The resulting suspension was stirred at room temperaturefor 2 h. After completion of reaction (monitored by TLC), reaction masswas filtered through a celite bed and the bed was washed with water(4000 mL). The combined filtrate was washed with ethyl acetate (2000 mL)and the organic layer was separated. The aqueous layer was acidifiedwith 1M hydrochloric acid solution to pH=1 and extracted with ethylacetate (10000 mL×3). The Combined organic layer was dried overanhydrous sodium sulfate and evaporated in vacuum to get crude titlecompound 2,2′-(1-((benzyloxy)carbonyl)pyrrolidine-3,4-diyl)diacetic acid(313 g, crude) as yellowish semisolid which was used for next stepwithout further purification. Calculated M+H: 322.33; Found M+H: 322.20.

Step-4: Preparation of benzyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a stirred solution of2,2′-(1-((benzyloxy)carbonyl)pyrrolidine-3,4-diyl)diacetic acid (313 g,0.975 mol) in acetic anhydride (1700 mL) was added sodium acetate (79.9g, 0.975 mol) under inert atmosphere and resulting suspension wasstirred at 120° C. for 3 h. After completion of reaction (monitored byTLC), the reaction mass was cooled to room temperature, filtered andwashed with ethyl acetate (1000 mL). The combined filtrate wasevaporated in vacuum to get crude product which was purified by columnchromatography using 100-200 mesh silica gel and 30% ethylacetate/hexane as eluent to afford the title compound benzyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (180 g,71.2% yield) as a white solid. Calculated M+H: 260.12; Found M+H:260.30.

Example 3—Preparation of 5-(o-tolyl)octahydrocyclopenta[c]pyrrol-5-ol

Step-1: Preparation of benzyl5-hydroxy-5-(o-tolyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a stirred solution of 1-bromo-2-methylbenzene (6.0 g, 35.08 mmol) indry tetrahydrofuran (100 mL) was added tert-BuLi (1.2 M in hexane, 32mL, 47.36 mmol) at −78° C. slowly under N₂. The reaction mixture wasstirred for 15 min at −78° C., then allowed to warm to −40° C. andstirred for 30 min. The reaction mixture was cooled to −78° C., asolution of benzyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(6.3 g, 24.55 mmol) in dry tetrahydrofuran was added drop wise at −78°C., stirred for 1 h at −78° C. and gradually allowed to warm to roomtemperature in 2 h. After completion of reaction (monitored by TLC), thereaction mixture was quenched with saturated solution of ammoniumchloride (100 mL) and the mixture extracted with ethyl acetate (250mL×2), dried over anhydrous sodium sulfate, concentrated to afford crudeproduct which was purified by silica gel column chromatography (35%ethylacetate/hexane) to obtain the title compound benzyl5-hydroxy-5-(o-tolyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(4.2 g, 49% yield) as a colorless semi solid. Calculated (M+H): 352.18;Found [(M+H)—H2O]: 334.2.

Step-2: Preparation of 5-(o-tolyl)octahydrocyclopenta[c]pyrrol-5-ol

To a stirred solution of benzyl5-hydroxy-5-(o-tolyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(7.5 g, 21.10 mmol) in ethanol (100 mL), was added 10% Pd/C (1.4 g)under N₂ atmosphere. The reaction was subjected to hydrogenation inballoon and stirred for 6 h. After completion of reaction (monitored byTLC), the mixture was filtered through celite bed, washed with methanol.The filtrate was concentrated under vacuum to obtain the title compound5-(o-tolyl)octahydrocyclopenta[c]pyrrol-5-ol (4.0 g (crude), 85% yield)as a pale yellow liquid. Calculated (M+H): 218.15; Found (M+H): 218.2:Example 4—Preparation of5-(3-methoxyphenyl)octahydrocyclopenta[c]pyrrol-5-ol

Step-1: Preparation of benzyl5-hydroxy-5-(3-methoxyphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a stirred solution of 1-bromo-3-methoxybenzene (10.0 g, 53.46 mmol)in dry tetrahydrofuran (100 mL) was added tert-BuLi (1.5M in hexane, 50mL, 74.80 mmol) at −78° C. slowly under N₂. The reaction mixture wasstirred for 15 min at −78° C., then allowed to warm to −40° C. andstirred for 30 min. The reaction mixture was cooled to −78° C., asolution of benzyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(10.39 g, 40.10 mmol) in dry tetrahydrofuran was added drop wise at −78°C., stirred for 1 h at −78° C. and gradually warmed to room temperaturein 2 h. After completion of reaction (monitored by TLC), the mixture wasquenched with saturated solution of ammonium chloride (150 mL) and themixture extracted with ethyl acetate (250 mL×3), dried over anhydroussodium sulfate, concentrated to afford the crude product which waspurified by silica gel column chromatography (60% ethylacetate/hexane)to obtain the title compound benzyl5-hydroxy-5-(3-methoxyphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(3.3 g, 22.41% yield) as a colorless semi solid. Calculated (M+H):368.18; Found (M+H): 368.2.

Step-2: Preparation of5-(3-methoxyphenyl)octahydrocyclopenta[c]pyrrol-5-ol

To a stirred solution of benzyl5-hydroxy-5-(3-methoxyphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(3.3 g, 367.43 mmol) in ethanol (50 mL), was added 10% Pd/C (0.7 g)under N₂ atmosphere. The reaction subjected to hydrogenation in balloonand stirred for 16 h. After completion of reaction, the reaction mixturewas filtered through celite bed, washed with methanol. The filtrate wasconcentrated under vacuum to obtain the title compound5-(3-methoxyphenyl)octahydrocyclopenta[c]pyrrol-5-ol (2.0 g, crude) as awhite solid. Calculated (M+H): 234.14; Found (M+H): 234.0.

Example 5—Preparation of5-(4-(tert-butyl)phenyl)octahydrocyclopenta[c]pyrrol-5-ol

Step-1: Preparation of benzyl5-(4-(tert-butyl)phenyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a stirred solution of 1-bromo-4-(tert-butyl)benzene (10.0 g, 46.92mmol) in dry tetrahydrofuran (100 mL) was added sec-BuLi (1.2M inhexane, 47 mL, 56.3 mmol) at −78° C. slowly under N₂ atmosphere. Thereaction mixture was stirred for 15 min at −78° C., then allowed to warmto −40° C. and stirred for 30 min. The reaction mixture was again cooledto −78° C., a solution of benzyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (12.15 g, 46.92mmol) in dry tetrahydrofuran was added drop wise at −78° C., stirred for1 h at −78° C. and gradually allowed to warm to room temperature in 2 h.After completion of reaction (monitored by TLC), the reaction mixturewas quenched with saturated solution of ammonium chloride (150 mL) andextracted with ethyl acetate (250 mL×3), dried over anhydrous sodiumsulfate, concentrated to afford crude product which was purified bysilica gel column chromatography (35% ethylacetate/hexane) to obtain thetitle compound benzyl5-(4-(tert-butyl)phenyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(5.05 g, 27% yield) as off-white solid. Calculated (M+H): 394.23; Found[(M+H)—H2O]: 376.3.

Step-2: Preparation of5-(4-(tert-butyl)phenyl)octahydrocyclopenta[c]pyrrol-5-ol

To a stirred solution of benzyl5-(4-(tert-butyl)phenyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(5.05 g, 12.8 mmol) in ethanol (500 mL), was added 10% Pd/C (1.0 g)under N₂ atmosphere. The reaction subjected to hydrogenation in balloonand stirred for 6 h. After completion of reaction, the mixture wasfiltered through celite bed, washed with methanol. The filtrate wasconcentrated under vacuum to obtain the title compound5-(4-(tert-butyl)phenyl)octahydrocyclopenta[c]pyrrol-5-ol (3.2 g(crude), 97% yield) as off white solid. Calculated (M+H): 260.19; Found(M+H): 260.3.

TABLE 1 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name M + H M + H

5-(4-cyanophenyl)-5-hydroxy- N-(4-methoxyphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 378.17 378.2

5-hydroxy-N-(4- methylphenyl)-5-phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 337.18 337.4

N-(3-chlorophenyl)-5- hydroxy-5-phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 357.13 357.3

5-hydroxy-5-phenyl-N-[3- (trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyrrole- 2-carboxamide 389.16 (M − H) 389.2 (M −H)

N-(4-fluorophenyl)-5-hydroxy- 5-phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 341.16 341.2

5-hydroxy-N-(3- methoxyphenyl)-5-phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 353.18 353.2

5-hydroxy-N-(4- methoxyphenyl)-5-(2- methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 367.19 367.2

5-hydroxy-5-(2- methylphenyl)-N-(4- methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 351.20 351.3

5-hydroxy-N-(3- methoxyphenyl)-5-(2- methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 367.19 367.3

N-(3-chlorophenyl)-5- hydroxy-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 369.14 (M − H) 369.2 (M −H)

5-hydroxy-5-(2- methylphenyl)-N-[3- (trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyrrole- 2-carboxamide 403.17 (M − H) 403.4 (M −H)

N-(4-fluorophenyl)-5-hydroxy- 5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 355.17 355.2

5-hydroxy-5-(3- methoxyphenyl)-N-(4- methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 367.19 367.2

N-(3-chlorophenyl)-5- hydroxy-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 385.14 (M − H) 385.2 (M −H)

5-hydroxy-5-(3- methoxyphenyl)-N-[3- (trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyrrole- 2-carboxamide 419.17 (M − H) 419.4 (M −H)

5-hydroxy-5-(3- methoxyphenyl)-N-(4- methoxyphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 383.19 383.2

5-hydroxy-N,5-bis(3- methoxyphenyl)- octahydrocyclopenta[c]pyrrole-2-carboxamide 381.19 (M − H) 381.3 (M − H)

N-(2,4-difluorophenyl)-5- hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrole- 2-carboxamide 359.15 359.2

N-[(1R)-1-(4- chlorophenyl)ethyl]-5- hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrole- 2-carboxamide 385.16 385.2

5-hydroxy-N-[(2- methoxyphenyl)methyl]-5- phenyl-octahydrocyclopenta[c]pyrrole- 2-carboxamide 367.19 367.3

Example 6—Preparation of methyl4-(5-hydroxy-5-(o-tolyl)octahydrocyclopenta[c]pyrrole-2-carboxamido)benzoate

To a solution of 5-phenyloctahydrocyclopenta[c]pyrrol-5-ol (0.040 g,0.19 mmol) in dichloromethane (2 mL) was added methyl4-isocyanatobenzoate (0.04 g, 0.22 mmol) and triethylamine (0.036 mL)and resulting suspension was stirred at room temperature for 18 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasdiluted with water (2 mL), extracted with dichloromethane (10 mL×2),dried over sodium sulfate and concentrated to afford the crude materialwhich was purified by prep HPLC (column: XSelect CSH C-18 Prep (19×250mm, 5 um), mobile phase: A—5 mM ammonium acetate, B— acetonitrile, flowmode: gradient, flow: 15 ml/min, gradientT/% B: 0/30, 0.5/30, 15/90,21/90, 21.5/30, 26/30).

TABLE 2 The following compounds were prepared by the method describedabove Calculated Found Structure IUPAC Name M + H M + H

5-hydroxy-N-(2-methoxy-5- methylphenyl)-5-(2- methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 381.21 381.37

N-[4-chloro-3- (trifluoromethyl)phenyl]-5- hydroxy-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 437.13 (M − H) 437.31 (M −H)

5-hydroxy-N,5-diphenyl- octahydrocyclopenta[c]pyrrole- 2-carboxamide321.17 (M − H) 321.33 (M − H)

N-(3-cyanophenyl)-5- hydroxy-5-phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 346.16 (M − H) 346.32 (M − H)

5-hydroxy-N-(2-methoxy-5- methylphenyl)-5-phenyl-octahydrocyclopenta[c]pyrrole- 2-carboxamide 367.19 367.34

methyl 4-[({5-hydroxy-5- phenyl- octahydrocyclopenta[c]pyrrol- 2-yl}carbonyl)amino]benzoate 379.17 (M − H) 379.38 (M − H)

5-hydroxy-5-(3- methoxyphenyl)-N-phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 353.18 (M − H ) 351.32 (M − H)

5-hydroxy-5-(2- methylphenyl)-N-phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 337.18 (M − H) 335.33 (M − H)

N-(3-cyanophenyl)-5- hydroxy-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 360.18 (M − H) 360.33 (M −H)

N-[4-chloro-3- (trifluoromethyl)phenyl]-5- hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrole- 2-carboxamide 423.12 423.28

5-hydroxy-N-(2-methoxy-5- methylphenyl)-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 397.20 397.44

N-[4-chloro-3- (trifluoromethyl)phenyl]-5- hydroxy-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 453.13 (M − H) 453.33 (M −H)

N,5-bis(4-fluorophenyl)-5- hydroxy- octahydrocyclopenta[c]pyrrole-2-carboxamide 357.15 (M − H) 357.34 (M − H)

5-(4-fluorophenyl)-5- hydroxy-N-(4- methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 353.17 (M − H) 353.37 (M −H)

5-(4-fluorophenyl)-5- hydroxy-N-(3- methoxyphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxmaide 371.17 371.37

5-(4-fluorophenyl)-5- hydroxy-N-[3- (trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyrrole- 2-carboxamide 407.15 (M − H) 407.37 (M −H)

N-(3-chlorophenyl)-5-(4- fluorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrole- 2-carboxamide 373.12 (M − H) 373.33 (M −H)

N-(3-cyanophenyl)-5-(4- fluorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrole- 2-carboxamide 334.15 (M − H) 364.37 (M −H)

5-(4-fluorophenyl)-5- hydroxy-N-(pyridin-3-yl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 342.15 342.33

5-(4-fluorophenyl)-5- hydroxy-N-(2-methoxy-5- methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 383.18 (M − H) 383.37 (M −H)

N-[4-chloro-3- (trifluoromethyl)phenyl]-5- (4-fluorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrole- 2-carboxamide 441.11 (M − H) 441.33 (M −H)

5-hydroxy-5-phenyl-N- (pyridin-3-yl)- octahydrocyclopenta[c]pyrrole-2-carboxamide 324.16 324.35

methyl 4-({[5-hydroxy-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyrrol- 2- yl]carbonyl}amino)benzoate 411.18411.35

5-hydroxy-5-(3- methoxyphenyl)-N-(pyridin- 3-yl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 354.17 354.37

N-(2,4-dimethylphenyl)-5- hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrole- 2-carboxamide 351.2 351.38

N-(2,4-dimethylphenyl)-5- hydroxy-5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 365.22 365.41

N-(2,4-dimethylphenyl)-5- hydroxy-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 381.21 381.41

methyl 4-({[5-(4-tert- butylphenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrol- 2- yl]carbonyl}amino)benzoate 435.24 (M −H) 435.5 (M − H)

5-(4-tert-butylphenyl)-5- hydroxy-N-(3- methoxyphenyl)-octahydrocyclopenta[c]pyrrole- 2-carboxamide 409.24 409.47

5-(4-tert-butylphenyl)-N-(3- cyanophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrole- 2-carboxamide 402.23 (M − H) 402.5 (M −H)

5-(4-tert-butylphenyl)-N-[4- chloro-3- (trifluoromethyl)phenyl]-5-hydroxy- octahydrocyclopenta[c]pyrrole- 2-carboxamide 479.18 (M − H)479.47 (M − H)

5-(4-tert-butylphenyl)-5- hydroxy-N-phenyl-octahydrocyclopenta[c]pyrrole- 2-carboxamide 379.23 379.47

5-(4-tert-butylphenyl)-5- hydroxy-N-[3- (trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyrrole- 2-carboxamide 445.22 (M − H) 445.47 (M −H)

5-(4-tert-butylphenyl)-N-(3- chlorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyrrole- 2-carboxamide 411.19 (M − H) 411.24 (M −H)

Example 7—Preparation ofrac-2-(2-hydroxy-2-phenylethyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol

Step-1:2-(5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-phenylethanone

To a stirred solution of 5-phenyloctahydrocyclopenta[c]pyrrol-5-ol (0.1g, 0.46 mmol) in dimethylformamide (5 mL) was added potassium carbonate(0.13 g, 0.98 mmol) and 2-bromo-1-phenylethanone (0.1 g, 0.54 mmol) atroom temperature. The reaction mixture was stirred at room temperaturefor 4 h. After completion of reaction (monitored by TLC), the reactionmixture was diluted with cold water (15 mL) and extracted withethylacetate (50 mL×3). The combined organic layer were washed with coldwater (25 mL×2), brine (25 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford the crude compound, whichwas purified by silica gel column chromatography (30% ethylacetate/hexane) to obtain the title compound2-(5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-phenylethanone(0.11 g, 73% yield) as a white solid. Calculated (M+H): 322.17; Found(M+H): 322.2.

Step-2: Preparation ofrac-2-(2-hydroxy-2-phenylethyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol

To a stirred solution of2-(5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-phenylethanone(0.05 g, 0.16 mmol) in ethanol (15 mL) was added sodium borohydride(0.059 g, 1.55 mmol) at room temperature and stirred for 6 h. Aftercompletion of reaction (monitored by TLC), the solvent was removed underreduced pressure. The residue was diluted with water (10 mL) andextracted with ethyl acetate (25 mL×3). The combined organic layer waswashed with water (10 mL×2), brine (10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford the crudecompound, which was purified by silica gel column chromatography (3%methanol/dichloromethane) to obtain the title compound2-(2-hydroxy-2-phenylethyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol(0.02 g, 40% yield) as off-white solid. Calculated (M+H): 324.19; Found(M+H): 324.4.

TABLE 3 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name M + H M + H

2-[5-hydroxy-5-(3-methoxyphenyl)- octahydrocyclopenta[c]pyrrol-2-yl]-1-phenylethan-1-one 352.18 352.3

rac-2-(2-hydroxy-2-phenylethyl)-5- (3-methoxyphenyl)-octahydrocyclopenta[c]pyrrole-5-ol 354.20 354.4

1-(3-fluorophenyl)-2-{5-hydroxy-5- phenyl-octahydrocyclopenta[c]pyrrol-2- yl}ethan-1-one 340.16 340.2

1-(3-fluorophenyl)-2-[5-hydroxy-5- (3-methoxyphenyl)-octahydrocyclopenta[c]pyrrol-2- yl]ethan-1-one 370.17 370.2

rac-2-[2-(3-fluorophenyl)-2- hydroxyethyl]-5-(3-methoxyphenyl)-octahydrocyclopenta[c]pyrrol-5-ol 372.19 372.2

rac-2-[2-(3-fluorophenyl)-2- hydroxyethyl]-5-phenyl-octahydrocyclopenta[c]pyrrol-5-ol 342.18 342.4

2-{5-hydroxy-5-phenyl- octahydrocyclopenta[c]pyrrol-2-yl}-1-(4-hydroxyphenyl)ethan-1-one 338.17 338.3

2-{5-hydroxy-5-phenyl- octahydrocyclopenta[c]pyrrol-2-yl}-1-(4-methoxyphenyl)ethan-1-one 352.18 352.2

rac-2-[2-hydroxy-2-(4- methoxyphenyl)ethyl]-5-phenyl-octahydrocyclopenta[c]pyrrol-5-ol 354.20 354.2

rac-2-[2-hydroxy-2-(4- hydroxyphenyl)ethyl]-5-phenyl-octahydrocyclopenta[c]pyrrol-5-ol 340.18 340.2

2-(5-hydroxy-5- phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-(2-hydroxypropan-2- yl)phenyl)ethanone 380.49 380.5

rac-2-(2-hydroxy-2-(4-(2- hydroxypropan-2-yl)phenyl)ethyl)-5-phenyloctahydrocyclopenta[c]pyrrol- 5-ol 382.50 382.5

Example 8—Preparation ofrac-5-(4-(tert-butyl)phenyl)-2-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol

To a solution of5-(4-(tert-butyl)phenyl)octahydrocyclopenta[c]pyrrol-5-ol (0.040 g, 0.15mmol) in dichloromethane (2 mL) was added 2-(2,4-dichlorophenyl)oxirane(0.031 g, 0.17 mmol) and triethylamine (0.041 mL, 0.295 mmol) andresulting solution was stirred at room temperature for 18 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasdiluted with water (2 mL) and extracted with dichloromethane (5 mL×2),washed with water (10 mL), brine (10 mL), dried over sodium sulfate andconcentrated under vacuum to afford thecrude-5-(4-(tert-butyl)phenyl)-2-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol which was purified by prep HPLC(Method: Column: XSelect CSH C-18 Prep (19×250 mm, 5 um), Mobile phase:A-5 mM ammonium acetate, B-Acetonitrile, Flow mode Gradient, Flow: 15ml/min, T/% B: 0.0/30, 0.5/30, 15.0/90, 21.0/90, 21.5/30, 26.0/30).

TABLE 5 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name M + H M + H

rac-5-(4-tert-butylphenyl)-2-[2-(3- fluorophenyl)-2-hydroxyethyl]-octahydrocyclopenta[c]pyrrol-5-ol 398.24 398.51

rac-2-{2-hydroxy-2-[3- (trifluoromethyl)phenyl]ethyl}-5-(2-methylphenyl)- octahydrocyclopenta[c]pyrrol-5-ol 406.19 406.44

rac-2-{2-hydroxy-2-[3- (trifluoromethyl)phenyl]ethyl}-5-(3-methoxyphenyl)- octahydrocyclopenta[c]pyrrol-5-ol 422.19 422.43

rac-2-[2-(2,4-dichlorophenyl)-2- hydroxyethyl]-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyrrol-5-ol 422.12 422.37

rac-5-(4-fluorophenyl)-2-{2- hydroxy-2-[3-(trifluoromethyl)phenyl]ethyl}- octahydrocyclopenta[c]pyrrol-5-ol 410.17410.41

rac-2-[2-(2,4-dichlorophenyl)-2- hydroxyethyl]-5-(4-fluorophenyl)-octahydrocyclopenta[c]pyrrol-5-ol 410.10 410.3

rac-2-[2-hydroxy-2-(3- methoxyphenyl)ethyl]-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyrrol-5-ol 384.21 384.41

rac-2-(1-hydroxy-1-(4- hydroxyphenyl)propan-2-yl)-5-(3-methoxyphenyl)octahydrocyclo- penta[c]pyrrol-5-ol 384.21 384.3

Example 9—Preparation of5-phenyl-2-(pyridin-2-yl)octahydrocyclopenta[c]pyrrol-5-ol

To a stirred solution of 5-phenyloctahydrocyclopenta[c]pyrrol-5-ol (0.15g, 0.74 mmol) in toluene (10 ml) was added 2-bromopyridine (0.11 g, 0.74mmol). The reaction mixture was purged with argon for 20 min. ThenPd(OAc)₂ (0.015 g, 0.074 mmol) and RuPhos (0.034 g, 0.074 mmol) wereadded under argon atmosphere, followed by the addition of Sodiumtert-butoxide. The reaction mixture was heated to 100° C. and stirredfor 2 h. After completion of reaction (monitored by TLC), the reactionmixture was allowed to cool to room temperature, filtered through celitebed and washed thoroughly with ethyl acetate. The filtrate wasconcentrated under vacuum. The residue was dissolved in ethyl acetate,the organic layer was washed with water (15 mL×2), brine (15 mL), driedover anhydrous sodium sulfate, concentrated under vacuum to obtain crudecompound, which was purified by silica gel column chromatography (4%methanol/dichloromethane) to obtain the title compound5-phenyl-2-(pyridin-2-yl)octahydrocyclopenta[c]pyrrol-5-ol (0.12 g, 92%yield) as a white solid. Calculated (M+H): 281.36; Found (M+H): 281.2.

TABLE 6 The following compounds were prepared by the method describedabove Calculated Found Structure IUPAC Name M + H M + H

5-(4-fluorophenyl)-2- (pyridin-2-yl)- octahydrocyclopenta[c]pyrrol- 5-ol299.15 299.3

5-(4-fluorophenyl)-2-[6- (trifluoromethyl)pyridin-2- yl]-octahydrocyclopenta[c]pyrrol- 5-ol 367.14 367.2

5-(2-methylphenyl)-2- (pyridin-2-yl)- octahydrocyclopenta[c]pyrrol- 5-ol295.17 295.2

5-phenyl-2-[6- (trifluoromethyl)pyridin-2- yl]-octahydrocyclopenta[c]pyrrol- 5-ol 349.14 349.2

5-(2-methylphenyl)-2-[6- (trifluoromethyl)pyridin-2- yl]-octahydrocyclopenta[c]pyrrol- 5-ol 363.16 363.2

2-(6-methylpyridin-2-yl)-5- phenyl- octahydrocyclopenta[c]pyrrol- 5-ol295.17 295.2

5-(2-methylphenyl)-2-(6- methylpyridin-2-yl)-octahydrocyclopenta[c]pyrrol- 5-ol 309.19 309.2

5-(4-fluorophenyl)-2-(6- methylpyridin-2-yl)-octahydrocyclopenta[c]pyrrol- 5-ol 313.16 313.2

5-(4-tert-butylphenyl)-2- (pyridin-2-yl)- octahydrocyclopenta[c]pyrrol-5-ol 337.22 337.3

5-(4-tert-butylphenyl)-2-(6- methylpyridin-2-yl)-octahydrocyclopenta[c]pyrrol- 5-ol 351.24 351.3

Example 10—Preparation ofrac-2-(1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol

Step-1: Preparation of 2-bromo-1-(4-hydroxyphenyl)propan-1-one

To stirred solution of 2-bromo-1-(4-hydroxyphenyl)propan-1-one (1.0 g,6.67 mmol) in acetic acid (2.5 mL) was added pyridinium tribromide (2.3g, 7.33 mmol) at room temperature and stirred for 3 h. After completionof reaction (monitored by TLC), the reaction mixture was diluted withcold water (100 mL) and stirred for 30 min, product get precipitated.The solid was filtered, washed thoroughly with water, dried to affordthe title compound 2-bromo-1-(4-hydroxyphenyl)propan-1-one (1.0 g, 66%yield) as a white solid and taken for next step without purification.Calculated (M+H): 228.98; Found (M+2H): 231.0.

Step-2: Preparation ofrac-2-((3aR,5r,6aS)-5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one

To a stirred solution of 5-phenyloctahydrocyclopenta[c]pyrrol-5-ol (0.15g, 0.74 mmol) in dimethylformamide (5 mL) was added potassium carbonate(0.13 g, 2.22 mmol) and 2-bromo-1-(4-hydroxyphenyl)propan-1-one (0.18 g,0.81 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 4 h. After completion of reaction (monitored by TLC),the reaction mixture was diluted with cold water (20 mL) and extractedwith ethylacetate (50 mL×3). The combined organic layer was washed withcold water (15 mL×3), brine (10 mL) dried over anhydrous sodium sulfateand concentrated under vacuum to afford the crude compound which waspurified by silica gel column chromatography (4%methanol/dichloromethane) to obtain the title compound5-(4-(tert-butyl)phenyl)-2-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol(0.02 g, 7% yield) as a white solid. Calculated (M+H): 352.18; Found(M+H): 352.2.

Step-3: Preparation ofrac-2-(1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol

To a mixture of lithium borohydride (0.043 g, 1.99 mmol), intetrahydrofuran (10 mL) was added2-(5-hydroxy-5-phenyloctahydropentalen-2-yl)-1-(4-hydroxyphenyl)propan-1-one(0.07 g, 0.12 mmol) at room temperature and stirred for 4 h. Aftercompletion of reaction (monitored by TLC), the mixture was quenched withice water (15 mL) and extracted with ethyl acetate (50 ml×3), thecombined organic layer was washed with water (15 mL), brine (10 mL),dried over anhydrous sodium sulfate, filtered and concentrated to affordthe crude compound, which was purified by silica gel columnchromatography (4% methanol/dichloromethane) to obtain the titlecompound2-(1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol(0.015 g, 21% yield) as off-white solid. Calculated (M+H): 354.20; Found(M+H): 354.3.

TABLE 7 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name M + H M + H

rac-2-[5-(4-fluorophenyl)-5- hydroxy- octahydrocyclopenta[c]pyrrol-2-yl]-1-(4- hydroxyphenyl)propan-1-one 370.17 370.2

rac-2-[5-(4-tert-butylphenyl)- 5-hydroxy- octahydrocyclopenta[c]pyrrol-2-yl]-1-(4- hydroxyphenyl)propan-1-one 406.25 (M − H) 406.5 (M − H)

rac-2-[5-hydroxy-5-(2- methylphenyl)- octahydrocyclopenta[c]pyrrol-2-yl]-1-(4- hydroxyphenyl)propan-1-one 366.20 366.3

rac-2-[1-hydroxy-1-(4- hydroxyphenyl)propan-2-yl]- 5-(2-methylphenyl)-octahydrocyclopenta[c]pyrrol- 5-ol 368.21 368.3

rac-5-(4-tert-butylphenyl)-2- [1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl]- octahydrocyclopenta[c]pyrrol- 5-ol 410.26410.3

Example 11—Preparation of2-(3-hydroxy-3-(4-hydroxyphenyl)propyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol

Step-1: Preparation of phenyl 3-chloropropanoate

A mixture of phenol (5 g, 53.1 mmol) and 3-chloropropanoyl chloride(8.09 g, 63.7 mmol) were taken in round bottomed flask. The resultingmixture was heated to 100° C. and stirred for 16 h. After completion ofreaction (monitored by TLC), the reaction mixture was allowed to cool toroom temperature, poured in to ice water (100 mL), extracted with ethylacetate (100 mL×3). The combined organic layer was washed with 1M sodiumhydroxide solution (100 mL×2), water (50 mL×2), brine (50 mL), driedover anhydrous sodium sulfate, filtered and concentrated under vacuum toafford crude compound which was purified by silica gel columnchromatography (5% ethyl acetate/hexane) to obtain the title compoundphenyl 3-chloropropanoate (2.5 g, 25% yield) as a colorless liquid. ¹HNMR (400 MHz, CdCl3) δ 7.38 (t, J=7.6 Hz, 2H), 7.24 (t, J=7.6 Hz, 1H),7.11 (t, J=10.4 Hz, 2H), 3.87 (t, J=6.4 Hz, 2H), 3.05 (t, J=6.8 Hz, 2H).

Step-2: Preparation of 3-chloro-1-(4-hydroxyphenyl)propan-1-one

A mixture of phenyl 3-chloropropanoate (1.0 g, 5.41 mmol) andtrifluoromethanesulfonic acid (2.4 g, 27.0 mmol) were taken in roundbottomed flask and stirred for 4 h. After completion of reaction(monitored by TLC), the mixture was concentrated under vacuum. Theresidue was diluted with ethyl acetate (100 mL), washed with 20% sodiumbicarbonate solution (20 mL×3), water (25 mL), dried over anhydroussodium sulfate, filtered and concentrated under vacuum to afford thecrude compound, which was purified by silica gel column chromatography(30% ethyl acetate/hexane) to obtain the title compound3-chloro-1-(4-hydroxyphenyl)propan-1-one (0.53 g, 53% yield) as a whitesolid. Calculated (M−H): 183.03; Found (M−H): 183.1.

Step-3: Preparation of3-(5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one

To a stirred solution of 5-phenyloctahydrocyclopenta[c]pyrrol-5-ol (0.2g, 0.98 mmol) in dimethylformamide (10 mL) was added potassium carbonate(0.34 g, 2.46 mmol) and 3-chloro-1-(4-hydroxyphenyl)propan-1-one (0.19g, 1.08 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 4 h. After completion of reaction (monitored byTLC), the reaction mixture was diluted with cold water (25 mL) andextracted with ethylacetate (50 mL×3). The combined organic layer waswashed with cold water (15 mL×3), brine (25 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford the crude compound which was purified by silica gel columnchromatography (5% methanol/dichloromethane) to obtain the titlecompound3-(5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one(0.15 g, 44% yield) as a white solid. Calculated (M+H): 352.18; Found(M+H): 352.3.

Step-4: Preparation of2-(3-hydroxy-3-(4-hydroxyphenyl)propyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol

To a stirred slurry of lithium borohydride (0.061 g, 2.85 mmol) intetrahydrofuran (10 mL) was added3-(5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one(0.1 g, 0.28 mmol) at room temperature and stirred for 4 h. Aftercompletion of reaction (monitored by TLC), the mixture was quenched withice water (10 mL) and extracted with ethyl acetate (50 ml×3), thecombined organic layer was washed with water (10 mL×2), brine (10 mL),dried over anhydrous sodium sulfate, filtered and concentrated to affordthe crude compound, which was purified by silica gel columnchromatography (8% methanol/dichloromethane) to obtain the titlecompound2-(3-hydroxy-3-(4-hydroxyphenyl)propyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol(0.052 g, 74% yield) as off-white solid. Calculated (M+H): 354.20; Found(M+H): 354.5.

Example 12—Preparation of2N-(4-methoxyphenyl)-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

Step-1: Preparation of benzyl5-phenyl-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a stirred solution of benzyl5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.0g, 5.93 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid(2.26 mL, 29.64 mmol) and triethylsilane (5 ml, 29.64 mmol) at 0° C.under argon atmosphere. The reaction mixture was allowed to roomtemperature and stirred for 12 h. After completion of reaction(monitored by TLC), the reaction mixture was concentrated under vacuum.The residue was dissolved in ethyl acetate (250 mL), washed with water(50 mL), brine (50 mL), dried over anhydrous sodium sulfate,concentrated under vacuum to obtain crude compound, which was purifiedby silica gel column chromatography (15% ethyl acetate/hexane) to obtainthe title compound benzyl5-phenyl-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(1.82 g, 96% yield) as a pale yellow liquid. Calculated (M+H): 320.16;Found (M+H): 320.2.

Step-2: Preparation of 5-phenyloctahydrocyclopenta[c]pyrrole

To a stirred solution of benzyl5-phenyl-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.8g, 0.56 mmol) in ethanol (20 mL), was added 10% Pd/C (0.5 g) under N₂atmosphere. The reaction was subjected to hydrogenation in balloon andstirred for 6 h at room temperature. After completion of reaction(monitored by TLC), the mixture was filtered through celite bed, washedwith methanol. The filtrate was concentrated under vacuum to obtain thetitle compound 5-phenyloctahydrocyclopenta[c]pyrrole (1.0 g (crude), 95%yield) as a colorless liquid. Calculated (M+H): 188.14; Found (M+H):188.2.

Step-3: Preparation ofN-(4-methoxyphenyl)-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

To a stirred solution of 5-phenyloctahydrocyclopenta[c]pyrrole (0.1 g,0.53 mmol) in dichloromethane (5 mL), was added diisopopyl ethylamine(0.22 mL, 1.60 mmol) and 1-isocyanato-4-methoxybenzene (0.087 g, 0.59mmol) at 0° C. The reaction mixture allowed to warm to room temperatureand stirred for 8 h. After completion of reaction (monitored by TLC),the reaction mixture was diluted with water (20 mL) and extracted withdichloromethane (30 mL×3). The combined organic layer was washed withbrine solution (10 mL), dried over anhydrous sodium sulfate andconcentrated under vacuum to afford the crude compound which waspurified by silica gel column chromatography (50% ethyl acetate/hexane),the column purified product was re-purified by preparative TLC to obtainthe title compoundN-(4-methoxyphenyl)-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide(0.1 g, 58% yield) as off-white solid. Calculated (M+H): 337.18; Found(M+H): 337.2.

TABLE 8 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name (M + H) (M + H)

N-(4-hydroxyphenyl)-5- phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 323.17 323.2

N-(4-fluorophenyl)-5- phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 325.16 325.2

N,5-diphenyl- octahydrocyclopenta[c]pyrrole- 2-carboxamide 307.17 307.33

methyl 4-[({5-phenyl- octahydrocyclopenta[c]pyrrol- 2-yl}carbonyl)amino]benzoate 365.18 365.36

N-(3-methoxyphenyl)-5- phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 337.18 337.37

5-phenyl-N-[3- (trifluoromethyl)phenyl]- octahydrocyclopenta[c]pyrrole-2-carboxamide 375.16 375.33

N-(3-chlorophenyl)-5- phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 341.13 341.32

N-(3-cyanophenyl)-5- phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 332.17 332.33

N-[4-chloro-3- (trifluoromethyl)phenyl]-5- phenyl-octahydrocyclopenta[c]pyrrole- 2-carboxamide 409.12 409.33

N-(2-methoxy-5- methylphenyl)-5-phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 351.20 351.38

N-(2,4-dimethylphenyl)-5- phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 335.20 335.39

5-phenyl-N-(pyridin-3-yl)- octahydrocyclopenta[c]pyrrole- 2-carboxamide308.17 308.36

N-[(2- methoxyphenyl)methyl]-5- phenyl- octahydrocyclopenta[c]pyrrole-2-carboxamide 351.20 351.3

N-[(1R)-1-(4- chlorophenyl)ethyl]-5- phenyl-octahydrocyclopenta[c]pyrrole- 2-carboxamide 369.17 369.4

Example 13—Preparation ofrac-4-(1-hydroxy-2-(5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol

Step-1:1-(4-hydroxyphenyl)-2-(5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

To a stirred solution of 5-phenyloctahydrocyclopenta[c]pyrrole (0.3 g,1.60 mmol) in dimethylformamide (10 mL) was added potassium carbonate(0.44 g, 3.20 mmol) and 2-bromo-1-(4-hydroxyphenyl)ethanone (0.34 g,1.60 mmol) at room temperature and the reaction mixture was stirred for4 h. After completion of reaction (monitored by TLC), the reactionmixture was diluted with cold water (25 mL) and extracted withethylacetate (50 mL×3). The combined organic layer was washed with coldwater (25 ml×3), brine (25 mL) dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to afford the crude compoundwhich was purified by silica gel column chromatography (30% ethylacetate/hexane) to obtain the title compound1-(4-hydroxyphenyl)-2-(5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(0.3 g, 63% yield) as a pale yellow solid. Calculated (M+H): 322.27;Found (M+H): 322.2.

Step-2:rac-4-(1-hydroxy-2-(5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol

To a stirred solution of1-(4-hydroxyphenyl)-2-(5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(0.1 g, 0.31 mmol) in ethanol was added sodium borohydride (0.058 g,1.55 mmol) at room temperature and stirred for 6 h. After completion ofreaction (monitored by TLC), the solvent was removed by vacuum and theresidue was diluted with water (15 mL) and extracted with ethyl acetate(25 mL×3). The combined organic layer was washed with water (15 mL),brine (15 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford the crude compound whichwas purified by silica gel column chromatography (3%methanol/dichloromethane) to obtain the title compound4-(1-hydroxy-2-(5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol(0.054 g, 50% yield) as off-white solid. Calculated (M+H): 324.19; Found(M+H): 324.3.

Example 14—Preparation ofrac-2-(5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3-(trifluoromethyl)phenyl)ethanol

To a solution of 5-phenyloctahydrocyclopenta[c]pyrrole (0.040 g, 0.21mmol) in dichloromethane (2 mL) was added2-(3-(trifluoromethoxy)phenyl)oxirane (0.044 g, 0.24 mmol) andtriethylamine (0.041 mL, 0.3 mmol) and resulting solution was stirred atroom temperature for 18 h. After completion of reaction (monitored byTLC), reaction mixture was diluted with water (2 mL) and extracted withdichloromethane (5 mL×2), washed with brine (10 mL), dried over sodiumsulfate and concentrated under vacuum to afford the crude2-(5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3-(trifluoromethyl)phenyl)ethanolwhich was purified by prep HPLC (column: XSelect CSH C-18 Prep (19×250mm, 5 um), mobile phase: A-5 mM ammonium acetate, B— acetonitrile, flowmode: gradient, flow: 15 ml/min, gradientT/% B: 0/30, 0.5/30, 15/90,21/90, 21.5/30, 26/30).

TABLE 9 The following compound was prepared by the method describedabove. Calculated Found Structure IUPAC Name (M + H) (M + H)

rac-1-(3-methoxyphenyl)-2- {5-phenyl- octahydrocyclopenta[c]pyrrol-2-yl}ethan-1-ol 338.20 338.38

Example 15—Preparation of(3aR,5r,6aS)-5-benzyl-N-(3-chlorophenyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

To a stirred solution of(3aR,5r,6aS)-5-benzyloctahydrocyclopenta[c]pyrrol-5-ol (0.05 g, 0.23mmol) in dichloromethane (5 mL), was added triethylamine (0.97 mL, 0.69mmol) and 1-chloro-3-isocyanatobenzene (0.038 g, 0.25 mmol) at 0° C. Thereaction mixture was allowed to warm to room temperature and stirred for8 h. After completion of the reaction (monitored by TLC), the reactionmixture was quenched with 50% sodium bicarbonate solution and extractedwith dichloromethane. The combined organic layer was washed with water,brine solution, dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford the crude compound which was purifiedby silica gel column chromatography (3% methanol/dichloromethane) toobtain the title compound(3aR,5r,6aS)-5-benzyl-N-(3-chlorophenyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide(0.056 g, 62% yield) as a white solid. Calculated (M+H): 371.14; Found(M+H): 371.2.

TABLE 10 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name (M + H) (M + H)

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(3- methoxyphenyl)hexahydro-cyclopenta[c]pyrrole- 2(1H)-carboxamide 367.19 367.4 

(3aR,5r,6aS)-5-benzyl- N-(4-chloro-3- (trifluoromethyl)phenyl)- 5-hydroxyhexahydrocyclo- penta[c]pyrrole-2(1H)- carboxamide 439.13 439.4 

(3aR,5r,6aS)-5-benzyl- N-(2,4-dimethylphenyl)- 5- hydroxyhexahydrocyclo-penta[c]pyrrole-2(1H)- carboxamide 365.22 365.49

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N- phenylhexahydrocyclo-penta[c]pyrrole-2(1H)- carboxamide 335.18 (M − H) 335.19 (M − H)

(3aR,5r,6aS)-5-benzyl- N-(3-cyanophenyl)-5- hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- carboxamide 360.18 (M − H) 360.23 (M − H)

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(2-methoxy- 5-methylphenyl)hexahydro- cyclopenta[c]pyrrole- 2(1H)-carboxamide 381.21381.21

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(p- tolyl)hexahydrocyclo-penta[c]pyrrole-2(1H)- carboxamide 351.2  351.4 

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(4- methoxyphenyl)hexahydro-cyclopenta[c]pyrrole- 2(1H)-carboxamide 367.19 367.3 

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(2- (trifluoromethyl)phenyl)hexahydrocyclopenta[c] pyrrole-2(1H)- carboxamide 405.17 405.2 

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(2- methoxyphenyl)hexahydro-cyclopenta[c]pyrrole- 2(1H)-carboxamide 367.19 367.2 

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(m- tolyl)hexahydrocyclopenta[c]pyrrole-2(1H)- carboxamide 351.2  351.2 

Example 16—Preparation ofrac-(3aR,5r,6aS)-5-benzyl-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol

Step 1: Preparation of2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone

To a stirred solution of(3aR,5r,6aS)-5-benzyloctahydrocyclopenta[c]pyrrol-5-ol (0.3 g, 1.38mmol) in dimethylformamide (10 mL), was added potassium carbonate (0.572g, 4.14 mmol) and 2-bromo-1-(4-hydroxyphenyl)ethanone (0.326 g, 1.51mmol) at room temperature and stirred for 6 h. After completion of thereaction (monitored by TLC), the reaction mixture was quenched with coldwater (50 mL) and extracted with ethyl acetate (100 mL×3). The combinedorganic layer was washed with cold water (50 mL), brine (50 mL), driedover anhydrous sodium sulfate, filtered and concentrated under vacuum toafford the crude compound which was purified by silica gel columnchromatography (35% ethyl acetate/hexane) to obtain the title compound2-((3 aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone(0.1 g, 20% yield) as off white solid. Calculated M+H: 352.18; FoundM+H: 352.3.

Step 2: Preparation ofrac-(3aR,5r,6aS)-5-benzyl-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol

To a stirred solution of2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone(0.080 g, 0.23 mmol) in ethanol (20 mL), was added sodium borohydride(0.043 g, 1.14 mmol) at room temperature and stirred for 2 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasconcentrated under vacuum and the residue was diluted with water (10 mL)and extracted with ethyl acetate (30 mL×3), The combined organic layerwas washed with water (10 mL×3), brine (15 mL), dried over anhydroussodium sulfate and concentrated under vacuum to afford the crudecompound which was purified by silica gel column chromatography (10%methanol/dichloromethane) to obtain the title compound(3aR,5r,6aS)-5-benzyl-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol(0.020 g, 25% yield) as off-white solid. Calculated M+H: 354.20; FoundM+H: 354.3.

Example 17—Preparation of 2-bromo-1-(5-hydroxypyridin-2-yl)ethanone

Step 1: Preparation of 5-hydroxypicolinoyl chloride

To a suspension of 5-hydroxypicolinic acid (1.0 g, 7.18 mmol) indichloromethane (70 mL) and catalytic amount of N,N-dimethyl formamide(0.2 mL), was added oxalyl chloride (1.25 mL, 14.37 mmol) slowly at 0°C., the resulting suspension was allowed to warm to room temperature andrefluxed for 16 h. The mixture was allowed to cool to room temperatureand concentrated under vacuum to afford the title compound5-hydroxypicolinoyl chloride (1.1 g, crude) which was as such taken fornext step without further purification.

Step 2: Preparation of 2-bromo-1-(5-hydroxypyridin-2-yl)ethanone

To a suspension of 5-hydroxypicolinoyl chloride (1.1 g, 7.18 mmol,crude) in dichloromethane: tetrahydrofuran mixture (1:1, 50 mL) wasadded trimethyl silyl diazomethane (9.5 mL, 19.04 mmol, 2M in hexane)slowly at 0° C. and the reaction mixture was stirred at room temperaturefor 2 h. The reaction mixture was cooled to 0° C. and aqueoushydrobromic acid (47%, 3 mL, 19.04 mmol) was added. The reaction mixturewas allowed to room temperature and stirred for 2 h. The solid formedwas filtered, the washed with dichloromethane, diethyl ether and driedto obtain the title compound 2-bromo-1-(5-hydroxypyridin-2-yl)ethanone(0.6 g, crude) as pale brown solid. Calculated M+H: 215.96; Found M+H:216.0.

Example 18—Preparation of2-bromo-1-(4-(2-hydroxypropan-2-yl)phenyl)ethanone

Step 1: Preparation of methyl 4-acetylbenzoate

To a solution of 4-acetylbenzoic acid (10 g, 60.91 mmol) in methanol (60mL) was added sulphuric acid (10 mL). The reaction mixture was heated at60° C. for 4 h. After completion of the reaction (as monitored by TLC),the solution was concentrated, the residue was dissolved in ethylacetate (600 mL) and washed with saturated sodium bicarbonate solution(200 mL). The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated. The crude was purified by silica gel columnchromatography using 10% ethyl acetate in hexane to afford the titlecompound methyl 4-acetylbenzoate (9 g, 82% yield) as yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.061 (s, 4H), 3.877 (s, 3H), 2.165 (s, 3H).

Step 2: Preparation of 1-(4-(2-hydroxypropan-2-yl)phenyl)ethanone

A solution of diisobutylaluminium hydride (5.26 mL, 0.926 mmol, 25% intoluene) was added to a suspension of N,O-dimethylhydroxylaminehydrochloride (0.82 g, 8.418 mmol) in diethyl ether/tetrahydrofuranmixture (1:1, 200 mL) at 0° C. under nitrogen atmosphere. The mixturewas stirred for 1 h allowing the temperature slowly to warm to roomtemperature. This solution was added to a 0 OC solution of methyl4-acetylbenzoate (1.5 g, 8.418 mmol) in diethyl ether (200 mL) andstirred at room temperature for 2 h. Then methyl magnesium bromide indiethyl ether (10 mL) was added at 0° C. and stirred at room temperaturefor 1 h. Additional methyl magnesium bromide (18 mL, 84.18 mmol) indiethyl ether was added and the reaction mixture was stirred at roomtemperature for 3.5 h. The reaction was quenched with saturated aqueousammonium chloride solution and extracted with ethyl acetate (100 mL×2).The combined organic layer was washed with brine (50 mL), dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified by silica gel column chromatography using 14% ethyl acetate inhexane to afford the title 1-(4-(2-hydroxypropan-2-yl)phenyl)ethanone(0.4 g, 26% yield) as colorless liquid. ¹H NMR (400 MHz, DMSO-d₆) δ7.884-7.863 (d, J=8.4 Hz, 2H), 7.593-7.572 (d, J=8.4 Hz, 2H), 5.133 (s,1H). 2.538 (s, 3H), 1.421 (s, 6H).

Step 3: Preparation of2-bromo-1-(4-(2-hydroxypropan-2-yl)phenyl)ethanone

To a solution of 1-(4-(2-hydroxypropan-2-yl)phenyl)ethanone (0.4 g, 2.24mmol) in acetic acid (5 mL) was added pyridinium tribromide (0.78 g,2.46 mmol). The reaction mixture was stirred at room temperature for 4h. The solution was concentrated, diluted with water (30 mL) and extractwith ethyl acetate (100 mL×3). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified by silica gel column chromatography using 15% ethyl acetate inhexane to afford the title compound2-bromo-1-(4-(2-hydroxypropan-2-yl)phenyl)ethanone (0.05 g, 8.6% yield)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.934-7.913 (d, J=8.4 Hz,2H), 7.619-7.559 (d, J=24 Hz, 2H), 5.222 (s, 1H), 4.873 (s, 2H), 1.424(s, 6H).

Example 19—Preparation of 1-bromo-3-(4-hydroxyphenyl)propan-2-one

To a stirred solution of 2-(4-hydroxyphenyl)acetic acid (1.5 g, 9.86mmol) in a mixture of dichloromethane (75 mL) andN,N-dimethylformaldehyde (0.1 mL), oxalyl chloride (2.11 mL, 24.65 mmol)was added at 0° C. and stirred at room temperature for 3 h undernitrogen atmosphere. The reaction mixture was evaporated under vacuum toget solid which was dissolved in a mixture oftetrahydrofuran:dichloromethane (150 mL, 1:1). Then(trimethylsilyl)diazomethane (67.1 mL, 49.3 mmol) was added at 0° C. andstirred at room temperature for 1 h. 48% aqueous hydrogen bromide wasadded at 0° C. and the reaction mixture was stirred at room temperaturefor 2 h. The organic layer was separated, dried over anhydrous sodiumsulfate and evaporated under vacuum to get crude which was purified bysilica gel flash column chromatography using 20% ethyl acetate in hexaneto afford the title compound 1-bromo-3-(4-hydroxyphenyl)propan-2-one(0.549 g, crude) as a brownish solid. The crude was as such taken fornext step without further purification.

Example 20—Preparation of 2-bromo-1-(3-fluoro-4-hydroxyphenyl) ethanone

To a suspension of 1-(3-fluoro-4-hydroxyphenyl) ethanone (2.0 g, 12.98mmol) in 33% hydrobromic acid in acetic acid (200 mL), was added asolution of bromine (0.53 mL, 10.389 mmol) in 20 mL of 33% hydrobromicacid in acetic acid at 0° C. and stirred at the same temperature for 3h. The reaction mixture was diluted with ice water (100 mL) and extractwith ethyl acetate (100 mL×3). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified by silica gel column chromatography using 3% ethyl acetate inhexane to afford the title compound 2-bromo-1-(3-fluoro-4-hydroxyphenyl)ethanone (1.5 g, 49.66% yield) as a white solid. Calculated M+H: 232.95;Found M+H: 233.0.

Example 21—Preparation of 2-bromo-1-(6-chloropyridin-3-yl)ethanone

Step-1: Preparation of 6-chloronicotinoyl chloride

To a suspension of 6-oxo-1,6-dihydropyridine-3-carboxylic acid (1.0 g,7.18 mmol) in dichloromethane (150 mL) and catalytical amount of DMF(0.5 mL), was added oxalyl chloride (1.25 mL, 14.37 mmol) slowly at 0°C., the resulting suspension was allowed to warm to room temperature andrefluxed for 16 h. The mixture was allowed to cool to room temperatureand the volatiles were removed by vacuum to afford 6-chloronicotinoylchloride (crude) which was taken to next step without purification.

Step-2: Preparation of 2-bromo-1-(6-chloropyridin-3-yl)ethanone

To a suspension of 6-chloronicotinoyl chloride (1.0 g, crude) indichloromethane: tetrahydrofuran mixture (30 mL, 1:1) was addedtrimethylsilyl diazomethane (2M in hexane, 9.5 mL, 25.38 mmol) slowly at0° C. The mixture was slowly allowed to warm to room temperature andstirred for 2 h. The solution was cooled to 0° C. and aqueoushydrobromic acid (47% in water, 3 mL, 19.04 mmol) was added slowly. Thereaction mixture was allowed to warm to room temperature and stirred for2 h. The mixture was diluted with dichloromethane (50 mL), washed with20% sodium bicarbonate solution (30 mL), water (30 mL), dried overanhydrous sodium sulfate, filtered and concentrated. The crude productwas purified by silica gel column chromatography using 15% ethyl acetatein hexane to obtain title compound2-bromo-1-(6-chloropyridin-3-yl)ethanone (0.98 g, 65% yield) as a whitesolid. Calculated M+H: 233.92; Found M+H: 234.1.

Example 22—Preparation of 6-(2-bromoacetyl)pyridazin-3(2H)-one

Step-1: Preparation of 6-(1-ethoxyvinyl)pyridazin-3(2H)-one

To a solution of 6-chloropyridazin-3(2H)-one (0.5 g, 3.83 mmol) andtributyl(1-ethoxyvinyl)stannane (1.42 mL, 4.21 mmol) in toluene (30 mL)argon was purged for 5 minutes. Tetrakis(triphenylphosphine)palladium(0)(0.22 g, 0.19 mmol) was added and the reaction mixture was heated at100° C. for 18 h. The solution was filtered through celite and filtratewas concentrated to afford the title compound6-(1-ethoxyvinyl)pyridazin-3(2H)-one (0.63 g, crude) as a brownish gum.Calculated (M+H): 167.07; Found (M+1): 167.3.

Step-2: Preparation of 6-(2-bromoacetyl)pyridazin-3(2H)-one

To a solution of 6-(1-ethoxyvinyl)pyridazin-3(2H)-one (0.63 g, 3.79mmol) in tetrahydrofuran: water mixture (20 ml: 4 mL) was addedN-bromosuccinimide (1.0 g, 5.69 mmol) and the reaction mixture wasstirred at room temperature for 1.5 h. The reaction mixture was dilutedwith water (20 mL) and extracted with ethyl acetate (30 mL×2). Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand concentrated to afford the crude product which was purified bysilica gel column chromatography (30% ethyl acetate/hexane) to obtainthe title compound 6-(2-bromoacetyl)pyridazin-3(2H)-one (0.41 g, 50%yield) as a brownish solid. Calculated (M+H): 216.95; Found (M+1):217.1.

Example 23—Preparation of2-bromo-1-(3,5-difluoro-4-hydroxyphenyl)ethanone

Step 1: Preparation of 1-(3,5-difluoro-4-hydroxyphenyl)ethanone

A solution of 1-(3,5-difluoro-4-methoxyphenyl)ethanone (0.1 g, 0.53mmol) in 47% hydrobromic acid (3 mL) was heated at 100° C. for 30 h. Thereaction mixture was cooled to room temperature, diluted with water (30mL) and extracted with dichloromethane (50 mL×3). The combined organiclayer was dried over anhydrous sodium sulfate, filtered andconcentrated. The crude was purified by silica gel column chromatographyusing 20% ethyl acetate in hexane to afford the title compound1-(3,5-difluoro-4-hydroxyphenyl)ethanone (0.08 g, 86% yield) as a whitesolid. Calculated M−H: 171.03; Found M−H: 171.1.

Step 2: Preparation of 2-bromo-1-(3,5-difluoro-4-hydroxyphenyl)ethanone

To a solution of 1-(3,5-difluoro-4-hydroxyphenyl)ethanone (0.08 g, 0.465mmol) in acetic acid (5 mL) was added pyridinium tribromide (0.163 g,0.511 mmol). The reaction mixture was stirred at room temperature for 4h. The solution was concentrated, diluted with water (20 mL) andextracted with ethyl acetate (50 mL×3). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Thecrude was purified by silica gel column chromatography using 80%dichloromethane in hexane to afford the title compound2-bromo-1-(3,5-difluoro-4-hydroxyphenyl)ethanone (0.07 g, 60% yield) asa white solid. Calculated M+H: 250.94; Found M+H: 251.0.

Example 24—Preparation of 1-(5-(benzyloxy)pyrazin-2-yl)-2-bromoethanone

Step 1: Preparation of 2-(benzyloxy)-5-bromopyrazine

To a solution 5-bromopyrazin-2-ol (0.5 g, 2.857 mmol) in toluene (20 mL)was added silver carbonate (1.574 g, 5.714 mmol) and stirred at roomtemperature for 5 minutes. Then benzyl bromide (0.47 ml, 3.428 mmol) wasadded drop wise and the reaction mixture was stirred at room temperaturefor 16 h. The suspension was filtered through celite, the filtrate wasdiluted with ethyl acetate (200 mL) and washed with water (50 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The crude was purified by silica gel column chromatographyusing 3% ethyl acetate in hexane to afford the title compound2-(benzyloxy)-5-bromopyrazine (0.3 g, 40% yield) as a white solid.Calculated M+H: 264.99; Found M+H: 265.0.

Step 2: Preparation of 2-(benzyloxy)-5-(1-ethoxyvinyl)pyrazine

To a solution 2-(benzyloxy)-5-bromopyrazine (0.3 g, 1.13 mmol) intoluene (15 mL) was added tributyl(1-ethoxyvinyl)stannane (0.382 g,1.131 mmol) and purged with argon for 20 minutes. Thentetrakis(triphenyphosphine)palladium(0) (0.065 g, 0.056 mmol) was addedand reaction mixture was stirred at 100° C. for 18 h. The suspension wasfiltered through celite and the filtrate was concentrated to afford thetitle compound 2-(benzyloxy)-5-(1-ethoxyvinyl)pyrazine (0.3 g, crude) asbrownish gum. The crude was as such taken for next step withoutpurification. Calculated M+H: 257.12; Found M+H: 257.1.

Step 3: Preparation of 1-(5-(benzyloxy)pyrazin-2-yl)-2-bromoethanone

To a solution of 2-(benzyloxy)-5-(1-ethoxyvinyl)pyrazine (0.3 g, 1.17mmol) in tetrahydrofuran: water mixture (7.5 mL: 2.5 mL) at 0° C. wasadded N-bromo succinimide (0.312 g, 1.755 mmol)) and the reactionmixture was stirred at room temperature for 1.5 h. The solution wasdiluted with water (30 mL) and extracted with diethyl ether (80 mL×3).The combined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated. The crude was purified by silica gel columnchromatography using 2.7% ethyl acetate in hexane to afford the titlecompound 1-(5-(benzyloxy)pyrazin-2-yl)-2-bromoethanone (0.12 g, 33%yield) as a white solid. Calculated M+H: 307; Found M+H: 307.0.

Example 25—Preparation of1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-bromoethanone

Step-1: Preparation ofN-methoxy-N-methyl-1H-benzo[d][1,2,3]triazole-5-carboxamide

To a mixture of 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (0.5 g, 3.1mmol), N,O-dimethylhydroxylamine hydrochloride (0.3 g, 3.1 mmol) indichloromethane (40 mL), HBTU (1.4 g, 3.7 mmol), triethylamine (0.94 g,9.3 mmol) and N,N-dimethylformaldehyde (5 mL) were added and thereaction mixture was stirred at room temperature for 18 h under nitrogenatmosphere. The reaction mixture was diluted with dichloromethane (100mL) and washed with ice cold water (25 mL). The organic layer was driedover anhydrous sodium sulfate, filtered and evaporated under vacuum toget crude which was purified by silica gel flash column chromatographyusing 5% methanol in dichloromethane to afford the title compoundN-methoxy-N-methyl-1H-benzo[d][1,2,3]triazole-5-carboxamide (0.61 g,95%) as yellowish gum. Calculated (M+H): 207.2; Found (M+1): 207.1.

Step-2: Preparation of 1-(1H-benzo[d][1,2,3]triazol-5-yl)ethanone

To a solution ofN-methoxy-N-methyl-1H-benzo[d][1,2,3]triazole-5-carboxamide (0.6 g, 2.91mmol) in a mixture of tetrahydrofuran (5 mL):diethyl ether (20 mL), 3Mmethyl magnesium bromide in diethyl ether (1.45 mL, 4.36 mmol) was addedat 0° C. and the reaction mixture was stirred at room temperature for 16h under nitrogen atmosphere. The reaction mixture was quenched withsaturated ammonium chloride solution (10 mL) and extracted with ethylacetate (300 mL×2). Then combined organic layer was dried over anhydroussodium sulfate, filtered and evaporated under vacuum to get crude whichwas purified by silica gel flash column chromatography using 5% methanolin dichloromethane to afford the title compound1-(1H-benzo[d][1,2,3]triazol-5-yl)ethanone (0.251 g, 53.5%) as off-whitesolid. Calculated (M+H): 162.16; Found (M+1): 162.1.

Step-3: Preparation of1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-bromoethanone

A mixture of 1-(1H-benzo[d][1,2,3]triazol-5-yl)ethanone (0.15 g, 0.93mmol) and 33% hydrogen bromide in acetic acid (10 mL) was cooled to 0°C. A solution of bromine (0.05 mL, 0.93 mmol) in 5 mL of 33% hydrogenbromide in acetic acid was added at 0° C. and the reaction mixture wasstirred at 0° C. for 3 h. The solution was quenched with ice cold water(30 mL) and extracted with ethyl acetate (100 mL×2). The combinedorganic layer was washed with saturated sodium bicarbonate solution (30mL), dried over anhydrous sodium sulfate and evaporated under vacuum toget crude which was purified by silica gel flash column chromatographyusing 2% methanol in dichloromethane to afford the title compound1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-bromoethanone (0.075 g, 33%) asoff-white solid. Calculated (M+H): 239.97; Found (M+1): 240.0.

Example 26—Preparation of(3aR,5r,6aS)-5-benzyl-5-methoxyoctahydrocyclopenta[c]pyrrole

Step 1: Preparation of (3aR,5r,6aS)-benzyl5-benzyl-5-methoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Sodium hydride (0.273 g, 60%, 6.82 mmol) was added to a solution of(3aR,5r,6aS)-benzyl5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.2g, 3.41 mmol) in N,N-dimethylformamide (15 mL) at 0° C. and the reactionmixture was stirred at room temperature for 30 minutes. The suspensionwas cooled to 0° C., added methyl iodide (0.425 mL, 6.82 mmol) andstirred at room temperature for 3 h. The reaction mixture was dilutedwith ice-water (25 mL) and extracted with ethyl acetate (30 mL×2). Thecombined organic extract was washed with water (30 mL), brine (30 mL),dried over anhydrous sodium sulfate and evaporated. The crude materialwas purified by combiflash purifier using 15% ethyl acetate in hexane toafford (3aR,5r,6aS)-benzyl5-benzyl-5-methoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as ayellow liquid (1.0 g, 80% yield). Calculated M+H: 366.2; Found M+H:366.2.

Step 2: Preparation of(3aR,5r,6aS)-5-benzyl-5-methoxyoctahydrocyclopenta[c]pyrrole

To a solution of (3aR,5r,6aS)-benzyl5-benzyl-5-methoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.0g, 2.73 mmol) in ethanol (25 mL) was added 10% Pd/C (0.1 g, 50% wet).The reaction mixture was degassed and hydrogenated under hydrogenbladder pressure for 2 h. The reaction mixture was filtered throughcelite and the filtrate was evaporated to afford the title compound(3aR,5r,6aS)-5-benzyl-5-methoxyoctahydrocyclopenta[c]pyrrole (0.6 g,crude) as yellow gum. Calculated M+H: 232.16; Found M+H: 232.2.

Example 27—Preparation of 2-bromo-1-(6-hydroxypyridin-3-yl)ethanone

Step-1: Preparation of N,6-dimethoxy-N-methylnicotinamide

To a mixture of 6-methoxynicotinic acid (2.0 g, 13.06 mmol) andN,O-dimethylhydroxylamine hydrochloride (1.42 g, 14.58 mmol) indichloromethane (20 mL), HBTU (6.6 g, 17.5 mmol), triethylamine (6 mL,43.7 mmol) and N,N-dimethylformaldehyde (5 mL) were added and thereaction mixture was stirred at room temperature for 18 h under nitrogenatmosphere. The reaction mixture was diluted with dichloromethane (50mL) and washed with ice cold water (25 mL). The organic layer was driedover anhydrous sodium sulfate, filtered and evaporated under vacuum toget crude which was purified by silica gel flash column chromatographyusing 5% methanol in dichloromethane to afford the title compoundN,6-dimethoxy-N-methylnicotinamide (1.2 g, 42%) as off-white solid.Calculated (M+H): 197.2; Found (M+1): 197.1.

Step-2: Preparation of 1-(6-methoxypyridin-3-yl)ethanone

To a solution of N,4-dimethoxy-N-methylbenzamide (1.4 g, 7.14 mmol) in amixture of tetrahydrofuran (5 mL):diethyl ether (100 mL), 3M methylmagnesium bromide in diethyl ether (4.75 mL, 4.27 mmol) was added at 0°C. and the reaction mixture was stirred at room temperature for 16 hunder nitrogen atmosphere. The solution was quenched with saturatedammonium chloride solution (20 mL) and extracted with ethyl acetate (100mL×2). The combined organic layer was dried over anhydrous sodiumsulfate and evaporated under vacuum to get crude which was purified bysilica gel flash column chromatography using 12% ethyl acetate in hexaneto afford the title compound 1-(6-methoxypyridin-3-yl)ethanone (0.825 g,77.1%) as off-white solid. Calculated (M+H): 152.16; Found (M+1): 152.1.

Step-3: Preparation of 1-(6-hydroxypyridin-3-yl)ethanone

A solution of 1-(6-methoxypyridin-3-yl)ethanone (0.65 g, 4.30 mmol) in33% hydrogen bromide in acetic acid (20 mL) was heated at 125° C. for 2h. The reaction mixture was quenched with ice cold water (50 mL) andextracted with ethyl acetate (100 mL×2). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and evaporated undervacuum to get the title compound 1-(6-hydroxypyridin-3-yl)ethanone (0.66g, 77.8%) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.078 (s,1H), 8.172 (d, 1H, J=2 Hz), 7.817 (dd, 1H, J=9.6 Hz, J=2.8 Hz), 6.335(d, 1H, J=10 Hz), 2.368 (s, 3H).

Step-4: Preparation of 2-bromo-1-(6-hydroxypyridin-3-yl)ethanone

A solution of 1-(6-hydroxypyridin-3-yl)ethanone (0.2 g, 1.46 mmol) in33% hydrogen bromide in acetic acid (15 mL) was cooled at 0° C., asolution of bromine (0.075 mL, 1.46 mmol) in 5 mL of 33% hydrogenbromide in acetic acid was added drop wise and stirred at 0° C. for 4 h.The reaction mixture was quenched with ice cold water (30 mL) andextracted with ethyl acetate (100 mL×3). The combined organic layer waswashed with saturated sodium bicarbonate solution (30 mL), dried overanhydrous sodium sulfate and evaporated under vacuum to get crude whichwas purified by silica gel flash column chromatography using 3% methanolin dichloromethane to afford the title compound2-bromo-1-(6-hydroxypyridin-3-yl)ethanone (0.175 g, 55.6%) as off-whitesolid. Calculated (M+H): 217.03; Found (M+1): 217.9.

Example 28—Preparation of 2-bromo-1-(5-hydroxypyrazin-2-yl)ethanone

Step 1: Preparation of 5-chloropyrazine-2-carboxylic acid

To a solution 5-hydroxypyrazine-2-carboxylic acid (10 g, 71.42 mmol) inthionyl chloride (100 mL) was added N, N-dimethyl formamide (1 mL) andthe reaction mixture was stirred at 80° C. for 16 h. Thionyl chloridewas distilled off, the residue was diluted with ice water and extractedethyl acetate (600 mL×3). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The crude wastriturated with diethyl ether to afford the title compound5-chloropyrazine-2-carboxylic acid (10.53 g, 93% yield) as a brownsolid. Calculated M+H: 158.99; Found M+H: 159.0.

Step 2: Preparation of 5-methoxypyrazine-2-carboxylic acid

To a solution 5-chloropyrazine-2-carboxylic acid (7 g, 44.15 mmol) inmethanol (55 mL) was added concentrated sulphuric acid (0.4 mL) andheated at 65° C. for 4 h. The reaction mixture was cooled to roomtemperature and diluted with methanol (15 mL). Then a solution of sodiummethoxide in methanol (8.58 g, 158.94 mmol, 35 mL) was added and thereaction mixture was stirred at room temperature for 30 minutes. Sodiumhydroxide (2.825 g, 70.643 mmol) in 30 ml water was added into thereaction mixture followed by addition of 40 mL water. Then the reactionmixture was heated at 40° C. for 1 h and concentrated to removemethanol. The residue was diluted with water, acidified with 38% aqueoushydrochloric acid solution (pH 2-3) and extracted ethyl acetate (600mL×3). The combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated to afford the title compound5-methoxypyrazine-2-carboxylic acid (6.43 g, 94% yield) as an orangesolid. Calculated M+H: 155.04; Found M+H: 155.1.

Step 3: Preparation of N,5-dimethoxy-N-methylpyrazine-2-carboxamide

To a solution of 5-methoxypyrazine-2-carboxylic acid (7.1 g, 46.09 mmol)and triethylamine (19.27, 138.28 mmol) in dichloromethane (250 mL) wereadded 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (13.48 g, 69.141mmol) and 1-hydroxybenzotriazole (7.472 g, 55.312 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 30 minutes. ThenN,O-dimethylhydroxylamine hydrochloride (13.488 g, 138.284 mmol) wasadded and the reaction mixture was stirred at room temperature for 16 h.The solution was diluted with dichloromethane (200 mL), washed withwater (200 mL), dried over anhydrous sodium sulphate, filtered andconcentrated. The crude was purified by silica gel column chromatographyusing 16% ethyl acetate in hexane to afford the title compoundN,5-dimethoxy-N-methylpyrazine-2-carboxamide (4.93 g, 54%) as a whitesolid. Calculated M+H: 198.08; Found M+H: 198.1.

Step 4: Preparation of 1-(5-methoxypyrazin-2-yl)ethanone

To a solution N,5-dimethoxy-N-methylpyrazine-2-carboxamide (4.93 g,25.01 mmol) in tetrahydrofuran (25 mL) and diethyl ether (100 ml) at 0°C. was added 3M methyl magnesium bromide in ether (12.49 ml, 37.5 mmol)drop wise. The reaction mixture was stirred at room temperature for 18h, quenched with saturated ammonium chloride solution and extracted withethyl acetate (300 mL×3). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated to afford the titlecompound 1-(5-methoxypyrazin-2-yl)ethanone (3.61 g, 94% yield) as ayellow solid. Calculated M+H: 153.06; Found M+H: 153.1.

Step 5: Preparation of 1-(5-hydroxypyrazin-2-yl)ethanone

A mixture of 1-(5-methoxypyrazin-2-yl)ethanone (0.1 g, 0.65 mmol) andsodium thiomethoxide (0.184 g, 2.628 mmol) in N, N-dimethyl formamide (4mL) was heated at 100° C. for 2 h. The reaction mixture was cooled toroom temperature, diluted with water (15 mL), acidified with 1.5 Maqueous hydrochloric acid solution (pH 2-3) and extracted with ethylacetate (60 mL×3). The combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated to afford1-(5-hydroxypyrazin-2-yl)ethanone (0.085 g, 94%) as a brownish solid.Calculated M+H: 139.04; Found M+H: 139.1.

Step 6: Preparation of 2-bromo-1-(5-hydroxypyrazin-2-yl)ethanone

To a solution of 1-(5-hydroxypyrazin-2-yl)ethanone (0.7 g, 5.06 mmol) inacetic acid (30 mL) was added pyridinium tribromide (1.782 g, 5.574mmol). The reaction mixture was stirred at room temperature for 3 h andconcentrated. The residue was diluted with water (50 mL) and extractedwith ethyl acetate (150 ml×3). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified by silica gel column chromatography using 2% methanol indichloromethane to afford the title compound2-bromo-1-(5-hydroxypyrazin-2-yl)ethanone (0.25 g, 22% yield) as ayellow solid. Calculated M+H: 216.95; Found M+H: 216.9.

Example 29—Preparation of2-bromo-1-(6-fluoro-5-hydroxypyridin-2-yl)ethanone

Step-1: Preparation of 6-bromo-2-fluoropyridin-3-ol

To a solution of 2-fluoropyridin-3-ol (1 g, 8.842 mmol) and sodiumacetate (0.72 g, 8.842 mmol) in acetic acid (10 mL) was added bromine(0.23 mL, 8.842 mmol) at 0° C. and the reaction mixture was stirred atroom temperature for 4 h. The solution was poured into ice, pH wasadjusted to 6 using 2N sodium hydroxide solution and extracted withethyl acetate (50 mL×2). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated to afford the crudeproduct, which was purified by silica gel column chromatography (10%ethyl acetate/hexane) to obtain the title compound6-bromo-2-fluoropyridin-3-ol (0.5 g, 30% yield) as a colorless liquid.Calculated (M+H): 193; Found (M+1): 193.9.

Step-2: Preparation of6-bromo-2-fluoro-3-((triisopropylsilyl)oxy)pyridine

To a solution of 6-bromo-2-fluoropyridin-3-ol (0.5 g, 2.604 mmol) intetrahydrofuran (20 mL) was added triethylamine (0.54 mL, 3.906 mmol)and the reaction mixture was cooled to 0° C. Chlorotriisopropylsilane(0.73 mL, 3.385 mmol) was added drop wise and the solution was stirredat room temperature for 2 h. The reaction mixture was diluted with water(30 mL) and extracted with ethyl acetate (50 ml×2). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto afford the crude product, which was purified by silica gel columnchromatography (5% ethyl acetate/hexane) to obtain the title compound6-bromo-2-fluoro-3-((triisopropylsilyl)oxy)pyridine (0.8 g, 87% yield)as a colorless liquid. Calculated (M+H): 348.07; Found (M+1): 348.1.

Step-3: Preparation of6-(1-ethoxyvinyl)-2-fluoro-3-((triisopropylsilyl)oxy)pyridine

To a solution of 6-bromo-2-fluoro-3-((triisopropylsilyl)oxy)pyridine(0.4 g, 1.148 mmol) and tributyl(1-ethoxyvinyl)stannane (0.43 mL, 1.263mmol) in toluene argon was purged for 10 minutes.Tetrakis(triphenylphosphine)palladium(0) was added and the reactionmixture was heated at 100° C. for 18 h. The solution was filteredthrough celite and filtrate was concentrated to afford the titlecompound 6-(1-ethoxyvinyl)-2-fluoro-3-((triisopropylsilyl)oxy)pyridine(0.36 g, crude) as brownish gum. Calculated (M+H): 340.5; Found (M+1):340.2.

Step-4: Preparation of2-bromo-1-(6-fluoro-5-hydroxypyridin-2-yl)ethanone

To a solution of6-(1-ethoxyvinyl)-2-fluoro-3-((triisopropylsilyl)oxy)pyridine (8.46 g,24.93 mmol) in tetrahydrofuran:water (280 ml, 3:1) mixture was addedN-bromosuccinimide and the reaction mixture was stirred at roomtemperature for 1.5 h. The reaction mixture was diluted with water (150mL) and extracted with ethyl acetate (300 ml×2). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto afford the crude product, which was purified by silica gel columnchromatography (40% ethyl acetate/hexane) to obtain the title compound2-bromo-1-(6-fluoro-5-hydroxypyridin-2-yl)ethanone (5.5 g, 95% yield) asbrownish gum. Calculated (M+H): 235.02; Found (M+1): 235.9.

Example 30—Preparation of 2-bromo-1-(6-chloropyridin-3-yl)ethanone

Step-1: Preparation of 2-chloro-5-((triisopropylsilyl)oxy)pyrimidine

To a solution of 2-chloropyrimidin-5-ol (1.0 g, 7.67 mmol) intetrahydrofuran (20 mL) was added triethylamine (2.15 mL, 15.34 mmol)and the reaction mixture was cooled to 0° C. Chlorotriisopropylsilane(2.46 mL, 11.50 mmol) was added drop wise and the solution was stirredat room temperature for 2 h. The reaction mixture was diluted with water(50 mL) and extracted with ethyl acetate (100 ml×2). The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to afford the crude product, which was purified by silicagel column chromatography using 5% ethyl acetate in hexane to obtain thetitle compound 2-chloro-5-((triisopropylsilyl)oxy)pyrimidine (1.9 g, 86%yield) as a colorless liquid. Calculated (M+H): 287.13; Found (M+1):287.1.

Step-2: Preparation of2-(1-ethoxyvinyl)-5-((triisopropylsilyl)oxy)pyrimidine

To a solution of 2-chloro-5-((triisopropylsilyl)oxy)pyrimidine (0.45 g,1.56 mmol) and tributyl(1-ethoxyvinyl)stannane (0.62 mL, 1.72 mmol) intoluene, argon was purged for 10 minutes.Tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.078 mmol) was addedand the reaction mixture was heated at 100° C. for 18 h. The solutionwas filtered through celite and filtrate was concentrated to afford thetitle compound 2-(1-ethoxyvinyl)-5-((triisopropylsilyl)oxy)pyrimidine(0.36 g, crude) as a brownish gum. Calculated (M+H): 323.21; Found(M+1): 323.3.

Step-3: Preparation of 2-bromo-1-(5-hydroxypyrimidin-2-yl)ethanone

To a solution of 2-(1-ethoxyvinyl)-5-((triisopropylsilyl)oxy)pyrimidine(0.5 g, 1.55 mmol) in tetrahydrofuran:water (10 ml, 3:1) mixture wasadded N-bromosuccinimide (0.41 g, 2.32 mmol) and the reaction mixturewas stirred at room temperature for 1.5 h. The reaction mixture wasdiluted with water (15 mL) and extracted with ethyl acetate (30 ml×2).The combined organic layer was dried over anhydrous sodium sulfate,filtered and concentrated to afford the crude product which was purifiedby silica gel column chromatography using 6% methanol in dichloromethaneto obtain the title compound 2-bromo-1-(5-hydroxypyrimidin-2-yl)ethanone(0.18 g) as brownish solid. Calculated (M+H): 216.95; Found (M+1):217.1.

Example 31—Preparation of (3aR,5r,6aS)-benzyl5-(2-fluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a suspension of activated magnesium turnings (0.598 g, 24.7 mmol) indry diethyl ether (25 mL) was added 2-fluorobenzyl bromide (4.3 g, 23.0mmol) and 1,2-dibromoethane (4 drops). The resulting mixture was stirredat room temperature until all magnesium turnings goes into the solution.To the above mixture was added a solution of benzyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.0 g,3.8 mmol) in diethyl ether (5 mL) at 0° C. and resulting suspension wasstirred at room temperature for 20 minutes. After completion of reaction(as monitored by TLC) the reaction mixture was quenched with saturatedammonium chloride solution (10 mL), extracted with ethyl acetate (100mL×3), washed with brine (100 mL), dried over Na₂SO₄ and concentratedunder vacuum to get the crude material which was purified by columnchromatography using 100-200 mesh silica gel with 40% ethyl acetate inhexane as eluent affording the title compound (3aR,5r,6aS)-benzyl5-(2-fluorobenzyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.800 g, 57% yield) as a white solid. Calculated M+H: 370.17; FoundM+H: 370.33.

Example 32—Preparation of (3aR,5r,6aS)-benzyl5-(cyclohexylmethyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Step-1: Preparation of (2′s,3aR,6aS)-benzyltetrahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxirane]-2(3H)-carboxylate

To a solution of benzyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.0 g,7.7 mmol) and trimethylsulphonium iodide (2.6 g, 13.1 mmol) indimethylsulfoxide (22 mL) was added a solution of potassium tertiarybutoxide (1.37 g, 12.3 mmol) in dimethylsulfoxide (26 mL) drop wise atroom temperature and the resulting mixture was stirred at roomtemperature for 16 h. After completion of reaction (as monitored byTLC), the reaction mixture was poured into ice-cold water (200 mL) andextracted with ether (150 mL×3). The combined ether layer was washedwith water (150 mL), brine (100 mL), dried over anhydrous sodiumsulfate, filtered and evaporated to obtain the title compound(2's,3aR,6aS)-benzyltetrahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxirane]-2(3H)-carboxylate(2.1 g, 77% yield) as light brown oil which was used for next stepwithout purification. Calculated M+H: 274.14; Found M+H: 274.18.

Step-2: Preparation of (3aR,5r,6aS)-benzyl5-(cyclohexylmethyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a suspension of copper iodide (0.695 g, 3.6 mmol) in tetrahydrofuran(35 mL) was added cyclohexylmagnesium bromide (4.5 mL, 2M intetrahydrofuran) at −10° C. and resulting suspension was stirred for 10min at same temperature. To the mixture was then added(2's,3aR,6aS)-benzyltetrahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxirane]-2(3H)-carboxylate(1 g, 3.6 mmol) in tetrahydrofuran (10 mL) via syringe and the resultingsolution was stirred at 0° C. for 1 h. After completion of reaction (asmonitored by TLC), the reaction mixture was quenched with saturatedammonium chloride solution (30 mL) and extracted with ethyl acetate (100mL×3). The combined ethyl acetate layer was washed with brine (100 mL),dried over sodium sulfate and evaporated under vacuum to obtain crudeproduct which was purified by column chromatography on silica gel using25% ethyl acetate in hexane as eluent to obtain title compound (3 aR,5r, 6aS)-benzyl5-(cyclohexylmethyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.900 g, 69%) as light yellow oil. Calculated M+H: 358.23; Found M+H:358.0.

Example 33—Preparation of(3aR,5r,6aS)-5-(thiophen-2-ylmethyl)octahydrocyclopenta[c]pyrrol-5-ol

Step-1: Preparation of benzyl(3aR,5r,6aS)-5-hydroxy-5-(thiophen-2-ylmethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of 2-bromothiophene (0.567 g, 3.5 mmol) in dry THF (20mL.) was added n-butyl lithium (2.5M in hexane, 1.4 mL, 3.5 mmol) at−78° C. (slowly drop wise) and resulting solution was stirred at −78° C.for 20 minutes. Then boron trifluoride etherate (0.30 mL, 2.9 mmol) wasadded. After 5 minutes a solution of benzyl(3aR,5S,6aS)-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxirane]-2(3H)-carboxylate(0.800 g, 2.9 mmol) in tetrahydrofuran (5.0 mL) was added and stirred at−78° C. for 15 minutes. The reaction mixture was then quenched withsaturated ammonium chloride solution (10 mL), extracted with ethylacetate (100 mL×3) washed with brine (100 mL), dried over sodium sulfateand concentrated to get the crude material which was purified by columnchromatography using 100-200 mesh silica with 20% ethyl acetate inhexane as eluent to obtain title compound benzyl(3aR,5r,6aS)-5-hydroxy-5-(thiophen-2-ylmethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.125 g, 12%) as off white solid. Calculated M+H: 358.14; Found M+H:358.24.

Step 2: Preparation of 5-(thiophen-2-ylmethyl)octahydrocyclopenta[c]pyrrol-5-ol

To a solution of benzyl5-hydroxy-5-(thiophen-2-ylmethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.34 g, 0.952 mmol) in tetrahydrofuran (15 mL) was added lithiumtriethylborohydride (4.7 mL, 4.76 mmol) at 0° C. and allowed thereaction mixture to stir at room temperature for 2 h. The solution wasquenched with saturated ammonium chloride solution and extracted withethyl acetate (50 mL×2). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated to afford the titlecompound 5-(thiophen-2-ylmethyl) octahydro cyclopenta[c]pyrrol-5-ol(0.18 g, 85.71% yield) as colorless liquid. Calculated M+H: 224.1; FoundM+H: 224.2.

Example 34—Preparation of (3aR,5r,6aS)-benzyl5-hydroxy-5-(pyridin-4-ylmethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

n-Butyl lithium (3.86 mL, 5.79 mmol, 1.5 M in hexane) was added dropwise to a solution of 4-methylpyridine (0.27 g, 2.89 mmol) intetrahydrofuran (15 mL) at −78° C. and the reaction mixture was stirredat 0° C. for 1 h. Then the reaction mixture was cooled to −78° C. andadded a solution of (3aR,6aS)-benzyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.5 g, 1.93 mmol)in tetrahydrofuran (10 mL). The solution was stirred at same temperaturefor one hour, warmed to room temperature, quenched with saturatedammonium chloride solution and extracted with ethyl acetate (50 mL×2).The combined organic extract was washed with water (35 mL), brine (35mL), dried over anhydrous sodium sulphate and evaporated. The crudematerial was purified by combiflash purifier using 3% methanol indichloromethane to afford the title compound (3 aR, 5r,6aS)-benzyl5-hydroxy-5-(pyridin-4-ylmethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.3 g, 44% yield) as a colorless gum. Calculated M+H: 353.23; FoundM+H: 353.2.

Example 35—Preparation of (3aR,5r,6aS)-benzyl5-(2-fluoropyridin-3-yl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

n-Butyl lithium (2.57 mL, 3.86 mmol, 1.5 M in hexane) was added dropwise to a solution of 3-bromo-2-fluoropyridine (0.5 g, 2.89 mmol) intetrahydrofuran (15 mL) at −78° C. and the reaction mixture was stirredat same temperature for 30 minutes. Then added a solution of(3aR,6aS)-benzyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.5 g, 1.93 mmol) in tetrahydrofuran (5 mL), stirred at sametemperature for one hour, warmed to room temperature and was stirred for15 h. Then the reaction mixture was quenched with saturated ammoniumchloride solution (30 mL) and extracted with ethyl acetate (50 mL×3).The combined organic extract was washed with water (50 mL), brine (50mL), dried over anhydrous sodium sulfate and evaporated. The crudematerial was purified by combiflash purifier using 60% ethyl acetate inhexane to afford the title compound (3aR,5r,6aS)-benzyl5-(2-fluoropyridin-3-yl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.2 g, 30% yield) as a yellow gum. Calculated M+H: 357.39; Found M+H:357.2.

Example 36—Preparation ofN-(6-(2-bromoacetyl)pyridin-3-yl)methanesulfonamide

Step 1: Preparation of N-(6-cyanopyridin-3-yl)methanesulfonamide

To a solution of 5-aminopicolinonitrile (0.5 g, 4.19 mmol) indichloromethane (40 mL) was added pyridine (1.0 mL, 12.57 mmol) and thesolution was cooled to 0° C. Methanesulfonyl chloride (0.32 mL, 4.19mmol) was added drop wise and the reaction mixture was stirred at roomtemperature for 18 h. The solution was diluted with dichloromethane (100mL), washed sequentially with 1.5M hydrochloric acid solution (30 mL)and brine solution (40 mL). The organic layer was dried over anhydroussodium sulfate, filtered and concentrated. The crude was purified bycombiflash column chromatography using 30% ethyl acetate in hexane toafford the title compound N-(6-cyanopyridin-3-yl)methanesulfonamide(0.18 g, 21% yield) as a brownish solid. Calculated M+H: 198.03; FoundM+H: 198.

Step 2: Preparation of N-(6-acetylpyridin-3-yl)methanesulfonamide

To a solution N-(6-cyanopyridin-3-yl)methanesulfonamide (0.5 g, 2.537mmol) in tetrahydrofuran:diethyl ether mixture (20 ml, 1:3) cooled at 0°C. was added 3M methyl magnesium bromide in ether (4.22 ml, 12.688 mmol)and the reaction mixture was stirred at room temperature for 18 h. Thesolution was quenched with saturated ammonium chloride solution andextracted with ethyl acetate (300 mL×3). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Thecrude was purified by column chromatography using 40% ethyl acetate inhexane to afford the title compoundN-(6-acetylpyridin-3-yl)methanesulfonamide (0.4 g, 73% yield) as ayellow solid. Calculated M+H: 215.04; Found M+H: 215.0.

Step 3: Preparation ofN-(6-(2-bromoacetyl)pyridin-3-yl)methanesulfonamide

To a solution of N-(6-acetylpyridin-3-yl)methanesulfonamide (1.5 g,7.008 mmol) in 33% hydrobromic acid in acetic acid (50 mL) was addedbromine (0.35 mL,7.008 mmol) dissolved in 33% hydrobromic acid in aceticacid (20 mL) drop wise at 0° C. and the reaction mixture was stirred atroom temperature for 7 h. The reaction mixture was diluted with diethylether, the solid formed was separated, dissolved in dichloromethane andwashed with saturated sodium bicarbonate solution. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Thecrude was purified by column chromatography using 30% ethyl acetate inhexane to afford the title compoundN-(6-(2-bromoacetyl)pyridin-3-yl)methanesulfonamide (0.51 g, 25% yield)as a yellow solid. Calculated M+H: 292.95; Found M+H: 292.9.

TABLE 11 The following compounds were prepared by the methods describedabove using intermediates made by the methods described above.Calculated Found Structure IUPAC Name (M + H) (M + H)

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(4- methoxyphenyl)ethanone 366.20 366.3

3-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl)propan- 1-one 366.20 366.3

2-((3aR,5r,6aS)-5-(4- fluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 370.17 370.4

rac-(3aR,5r,6aS)-5-(4- fluorobenzyl)-2-(2- hydroxy-2-(4-hydroxyphenyl)ethyl) octahydrocyclopenta[c] pyrrol-5-ol 372.19 372.5

(3aR,5R,6aS)-5- benzyl-2-((R)-2- hydroxy-2-(4- hydroxyphenyl)ethyl)octahydrocyclopenta[c] pyrrol-5-ol 354.2  354.5

(3aR,5S,6aS)-5- benzyl-2-((S)-2- hydroxy-2-(4- hydroxyphenyl)ethyl)octahydrocyclopenta[c] pyrrol-5-ol 354.2  354.5

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(4-(2- hydroxypropan-2- yl)phenyl)ethanone 394.23 394.3

rac-(3aR,5r,6aS)-5- benzyl-2-(2-hydroxy- 2-(4-(2- hydroxypropan-2-yl)phenyl)ethyl)octahydro- cyclopenta[c]pyrrol- 5-ol 396.25 396.6

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[clpyrrol-2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 353.18 353.2

N-(4-(2-((3aR,5r,6aS)- 5-benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)- yl)acetyl)phenyl)acetamide 393.21 393.5

(3aR,5R,6aS)-5- benzyl-2-((R)-2- hydroxy-2-(4- hydroxyphenyl)ethyl)octahydrocyclopenta[c] pyrrol-5-ol 354.20 354.5

(3aR,5S,6aS)-5- benzyl-2-((S)-2- hydroxy-2-(4- hydroxyphenyl)ethyl)octahydrocyclopenta[c] pyrrol-5-ol 354.20 354.5

rac-(3aR,5r,6aS)-5- benzyl-2-(2-hydroxy- 2-(5-hydroxypyridin- 2-yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 355.19 355.2

1-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-3-(4- hydroxyphenyl)propan- 2-one 366.47 366.5

N-(4-(2-((3aR,5r,6aS)- 5-benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)- yl)acetyl)phenyl)methane- sulfonamide 429.54429.5

5-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)- yl)acetyl)indolin-2- one 391.42 391.5

6-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)acetyl)-3,4- dihydroquinolin- 2(1H)-one 405.5  405.2

rac-N-(4-(2- ((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenyl) acetamide 395.23 395.6

rac-N-(4-(2- ((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenyl) methanesulfonamide431.56 431.5

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(3-fluoro- 4- hydroxyphenyl)ethanone 370.43 370.5

rac-5-(2- ((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)indolin- 2-one 393.49 393.3

rac-6-(2- ((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)-3,4- dihydroquinolin-2(1H)-one 407.52 407.5

rac-6-(2- ((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)benzo[d] oxazol-2(3H)-one395.19 395.5

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(6- chloropyridin-3- yl)ethanone 369.4  (M − H) 369.4 (M −H)

rac-(3aR,5S,6aS)-5- benzyl-2-((S)-2-(3- fluoro-4- hydroxyphenyl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol- 5-ol 372.45 372.5

6-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)- yl)acetyl)pyridazin- 3(2H)-one 354.17 354.5

rac-6-(2- ((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridazin- 3(2H)-one 356.19356.5

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(3,5- difluoro-4- hydroxyphenyl)ethanone 388.42 388.4

rac-(3aR,5r,6aS)-5- benzyl-2-(2-(3,5- difluoro-4- hydroxyphenyl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol- 5-ol 390.44  390.44

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(6- methoxypyridin-3- yl)ethanone 367.19 367.2

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(5- (benzyloxy)pyrazin-2- yl)ethanone 444.54 444.2

rac-(3aR,5r,6aS)-5- benzyl-2-(2-(5- (benzyloxy)pyrazin-2- yl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol- 5-ol 446.55 446  

(3aR,5S,6aS)-5- benzyl-2-((S)-2- hydroxy-2-(5- hydroxypyridin-2-yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 355.19 355.2

(3aR,5R,6aS)-5- benzyl-2-((R)-2- hydroxy-2-(5- hydroxypyridin-2-yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 355.19 355.2

2-((3aR,5r,6aS)-5-(4- fluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 371.41371.2

2-[(3aR,5R,6aS)-5- benzyl-5-hydroxy- octahydrocyclopenta[c]pyrrol-2-yl]-1-(1H- 1,2,3-benzotriazol-5- yl)ethan-1-one 377.45 377.5

rac-(3aR,5r,6aS)-5-(4- fluorobenzyl)-2-(2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 373.43373.2

1-(3-fluoro-4- hydroxyphenyl)-2- ((3aR,5r,6aS)-5-(4- fluorobenzyl)-5-hydroxyhexahydrocyclo- penta[c]pyrrol- 2(1H)-yl)ethanone 388.42 388.2

2-((3aR,5r,6aS)-5- benzyl-5- methoxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(3-fluoro- 4- hydroxyphenyl)ethanone 384.46 384.2

rac-(3aR,5r,6aS)-2-(2- (3-fluoro-4- hydroxyphenyl)-2-hydroxyethyl)-5-(4- fluorobenzyl)octahydro- cyclopenta[c]pyrrol- 5-ol390.44 390.5

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(3-fluoro- 4-(2-(3-fluoro-4- hydroxyphenyl)-2-oxoethoxy)phenyl) ethanone 522.55 522.5

2-(2-fluoro-4-(2- ((3aR,5r,6aS)-5-(4- fluorobenzyl)-5-hydroxyhexahydrocyclo- penta[c]pyrrol- 2(1H)- yl)acetyl)phenoxy)-1-(3-fluoro-4- hydroxyphenyl)ethanone 540.54 540.2

2-((3aR,5r,6aS)-5- benzyl-5- methoxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 366.47 366.3

rac-4-(2- ((3aR,5r,6aS)-5- benzyl-5- methoxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)-2- fluorophenol 386.47 386.2

rac-4-(2- ((3aR,5r,6aS)-5- benzyl-5- methoxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)phenol 368.48 368.2

rac-6-(2- ((3aR,5r,6aS)-5- benzyl-5- methoxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin- 3-ol 369.47 369.2

2-[(3aR,5R,6aS)-5- benzyl-5-hydroxy- octahydrocyclopenta[c]pyrrol-2-yl]-1-(6- hydroxypyridin-3- yl)ethan-1-one 351.43 (M − H)351.4 (M − 1)

2-((3aR,5r,6aS)-5- hydroxy-5-(4- methylbenzyl)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 366.47366.23

(3aR,5R,6aS)-5- benzyl-2-((R)-2-(3- fluoro-4- hydroxyphenyl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol- 5-ol 372.45 372.5

(3aR,5S,6aS)-5- benzyl-2-((S)-2-(3- fluoro-4- hydroxyphenyl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol- 5-ol 372.45 372.5

rac-5-{2- [(3aR,5R,6aS)-5- benzyl-5-hydroxy- octahydrocyclopenta[c]pyrrol-2-yl]-1- hydroxyethyl}pyridin- 2-ol 355.44 355.2

rac-(3aR,5R,6aS)-2- [2-hydroxy-2-(4- hydroxyphenyl)ethyl]- 5-[(4-methylphenyl)methyl]- octahydrocyclopenta[c] pyrrol-5-ol 368.48  368.22

2-((3aR,5r,6aS)-5- hydroxy-5-(2- methylbenzyl)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 366.47 366.21

2-[(3aR,5R,6aS)-5- hydroxy-5-[(4- methoxyphenyl)methyl]-octahydrocyclopenta [c]pyrrol-2-yl]-1-(4- hydroxyphenyl)ethan- 1-one382.19  382.10

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)- 5-(2-methylbenzyl)octahydro- cyclopenta[c]pyrrol- 5-ol 368.48  368.25

rac-(3aR,5R,6aS)-2- [2-(1H-1,2,3- benzotriazol-5-yl)-2- hydroxyethyl]-5-benzyl- octahydrocyclopenta[c] pyrrol-5-ol 379.47 379.5

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(5- hydroxypyrazin-2- yl)ethanone 354.41 354.2

rac-(3aR,5r,6aS)-5- benzyl-2-(2-hydroxy- 2-(5-hydroxypyrazin- 2-yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 356.43 356.2

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)- 5-(4-methoxybenzyl)octahydro- cyclopenta[c]pyrrol- 5-ol 384.48  384.37

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(6-fluoro- 5-hydroxypyridin-2- yl)ethanone 371.42 371.2

rac-(3aR,5r,6aS)-5- benzyl-2-(2-(6-fluoro- 5-hydroxypyridin-2- yl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol- 5-ol 373.43 373.3

2-[(3aR,5R,6aS)-5- hydroxy-5-[(4- methoxyphenyl)methyl]-octahydrocyclopenta [c]pyrrol-2-yl]-1-(5- hydroxypyridin-2-yl)ethan-1-one 383.45 383.4

2-((3aR,5r,6aS)-5- hydroxy-5-(3- methoxybenzyl)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone383.19 383.3

2-((3aR,5r,6aS)-5- hydroxy-5-(3- methoxybenzyl)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 382.19 382.2

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)- 5-(3-methoxybenzyl)octahydro- cyclopenta[c]pyrrol- 5-ol 384.21 384.4

rac-((3aR,5r,6aS)-2- (2-hydroxy-2-(5- hydroxypyridin-2- yl)ethyl)-5-(3-methoxybenzyl)octahydro- cyclopenta[c]pyrrol- 5-ol 385.2  385.2

2-((3aR,5r,6aS)-5- benzyl-5- methoxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(6-fluoro- 5-hydroxypyridin-2- yl)ethanone 385.44 385.2

rac-6-(2- ((3aR,5r,6aS)-5- benzyl-5- methoxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)-2- fluoropyridin-3-ol 387.46387.2

rac-6-{2- [(3aR,5R,6aS)-5- hydroxy-5-[(4- methoxyphenyl)methyl]-octahydrocyclopenta[c] pyrrol-2-yl]-1- hydroxyethyl}pyridin- 3-ol 385.47385.5

1-(6-fluoro-5- hydroxypyridin-2-yl)- 2-((3aR,5r,6aS)-5- hydroxy-5-(3-methoxybenzyl)hexahydro- cyclopenta[c]pyrrol- 2(1H)-yl)ethanone 401.18401.2

rac-(3aR,5r,6aS)-2-(2- (6-fluoro-5- hydroxypyridin-2-yl)-2-hydroxyethyl)-5-(3- methoxybenzyl)octahydro- cyclopenta[c]pyrrol- 5-ol403.2  403.2

2-[(3aR,5R,6aS)-5- benzyl-5-hydroxy- octahydrocyclopenta[c]pyrrol-2-yl]-1-(5- hydroxypyrimidin-2- yl)ethan-1-one 354.17 354.2

rac-2-{2- [(3aR,5R,6aS)-5- benzyl-5-hydroxy- octahydrocyclopenta[c]pyrrol-2-yl]-1- hydroxyethyl}pyrimidin- 5-ol 356.19 356.5

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)-5-(thiophen-2- ylmethyl)octahydrocyclo- penta[c]pyrrol-5-ol 360.48 360.3

2-[(3aR,5R,6aS)-5- (cyclohexylmethyl)-5- hydroxy- octahydrocyclopenta[c]pyrrol-2-yl]-1-(4- hydroxyphenyl)ethan- 1-one 358.49 358.2

2-[(3aR,5R,6aS)-5- (cyclohexylmethyl)-5- hydroxy- octahydrocyclopenta[c]pyrrol-2-yl]-1-(5- hydroxypyridin-2- yl)ethan-1-one 359.47 359.2

2-((3aR,5r,6aS)-5- (cyclopropylmethyl)- 5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 317.18317.2

rac-6-{2- [(3aR,5R,6aS)-5-[(3,5- dimethylphenyl)methyl]- 5-hydroxy-octahydrocyclopenta[c] pyrrol-2-yl]-1- hydroxyethyl}pyridin- 3-ol-3-ol383.5  383.5

rac-(3aR,5R,6aS)-5- (cyclohexylmethyl)-2- [2-hydroxy-2-(4-hydroxyphenyl)ethyl]- octahydrocyclopenta [c]pyrrol-5-ol 360.5  360.5

2-((3aR,5r,6aS)-5- (cyclopropylmethyl)- 5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 316.18 316.2

rac-(3aR,5r,6aS)-5- (cyclopropylmethyl)- 2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl) octahydrocyclopenta[c] pyrrol-5-ol 318.2  318.3

2-[(3aR,5R,6aS)-5- [(3,5- dimethylphenyl)methyl]- 5-hydroxy-octahydrocyclopenta [c]pyrrol-2-yl]-1-(4- hydroxyphenyl)ethan- 1-one380.49 380.2

rac-(3aR,5R,6aS)-5- [(3,5- dimethylphenyl)methyl]- 2-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]- octahydrocyclopenta[c] pyrrol-5-ol 382.51 382.2

rac-6-{2- [(3aR,5R,6aS)-5- (cyclohexylmethyl)-5- hydroxy-octahydrocyclopenta[c] pyrrol-2-yl]-1- hydroxyethyl}pyridin- 3-ol 361.49361.2

rac-2-(2-hydroxy-2- (5-hydroxypyridin-2- yl)ethyl)-5-(thiophen- 2-ylmethyl)octahydrocyclo- penta[c]pyrrol-5-ol 361.15 361.2

2-[(3aR,5R,6aS)-5- hydroxy-5-{[4- (trifluoromethyl)phenyl] methyl}-octahydrocyclopenta[c] pyrrol-2-yl]-1-(5- hydroxypyridin-2-yl)ethan-1-one 421.42 421.3

rac-6-{2- [(3aR,5R,6aS)-5- hydroxy-5-{[4- (trifluoromethyl)phenyl]methyl}- octahydrocyclopenta [c]pyrrol-2-yl]-1- hydroxyethyl}pyridin-3-ol 423.44 423.3

2-((3aR,5r,6aS)-5-(4- chlorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 387.14387.1

2-[(3aR,5R,6aS)-5- hydroxy-5-{[4- (trifluoromethyl)phenyl] methyl}-octahydrocyclopenta [c]pyrrol-2-yl]-1-(4- hydroxyphenyl)ethan- 1-one420.44 420.2

1-(3-fluoro-4- hydroxyphenyl)-2-(5- hydroxy-5-(thiophen- 2-ylmethyl)hexahydrocyclo- penta[c]pyrrol- 2(1H)-yl)ethanone 376.13 376.3

2-(5-(2-fluorobenzyl)- 5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 371.17 371.5

rac-2-(2-(3-fluoro-4- hydroxyphenyl)-2- hydroxyethyl)-5- (thiophen-2-ylmethyl)octahydro- cyclopenta[c]pyrrol-5-ol 378.15 378.3

rac-(3aR,5r,6aS)-5- (4-chlorobenzyl)-2-(2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 389.16389.2

rac-(3aR,5R,6aS)-2- [2-hydroxy-2-(4- hydroxyphenyl)ethyl]- 5-{[4-(trifluoromethyl)phenyl] methyl}- octahydrocyclopenta[c] pyrrol-5-ol422.45 422.2

2-((3aR,5r,6aS)-5-(2- fluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 370.43 370.2

2-((3aR,5r,6aS)-5- hydroxy-5-(pyridin-4- ylmethyl)hexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 353.43 353.5

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)- 5-(pyridin-4-ylmethyl)octahydrocyclo- penta[c]pyrrol-5-ol 354.44 355.5

rac-5-(2- fluorobenzyl)-2-(2- hydroxy-2-(5- hydroxypyridin-2-yl)ethyl)octahydrocyclo- penta[c]pyrrol-5- olyl)ethanone 373.18 373.2

rac-(3aR,5r,6aS)-5-(2- fluorobenzyl)-2-(2- hydroxy-2-(4-hydroxyphenyl)ethyl) octahydrocyclopenta[c] pyrrol-5-ol 372.45 372.2

2-((3aR,5r,6aS)-5- (2,4-difluorobenzyl)- 5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 389.41389.2

2-((3aR,5r,6aS)-5- hydroxy-5-(pyridin-2- ylmethyl)hexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 353.43 353.5

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)- 5-(pyridin-2-ylmethyl)octahydrocyclo- penta[c]pyrrol-5-ol 355.44 355.4

rac-(3aR,5r,6aS)-5- (2,4-difluorobenzyl)- 2-(2-hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 391.42391.2

2-((3aR,5r,6aS)-5-(2- chlorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 387.14387.1

N-(6-(2-((3aR,5r,6aS)- 5-benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)- yl)acetyl)pyridin-3- yl)methanesulfonamide 430.53430.2

rac-N-(6-(2- ((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1- hydroxyethyl)pyridin- 3-yl)methanesulfonamide 432.55 432.2

2-[(3aR,5R,6aS)-5- [(2,6- difluorophenyl)methyl]- 5-hydroxy-octahydrocyclopenta[c] pyrrol-2-yl]-1-(5- hydroxypyridin-2-yl)ethan-1-one 389.41 389.2

2-(5-(2,4- difluorobenzyl)-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 388.16 388.2

2-((3aR,5r,6aS)-5- (3,4-difluorobenzyl)- 5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 389.41389.1

rac-6-{2- [(3aR,5R,6aS)-5-[(2,6- difluorophenyl)methyl]- 5-hydroxy-octahydrocyclopenta[c] pyrrol-2-yl]-1- hydroxyethyl}pyridin- 3-ol 391.42391.2

2-[(3aR,5R,6aS)-5- [(2,6- difluorophenyl)methyl]- 5-hydroxy-octahydrocyclopenta[c] pyrrol-2-yl]-1-(4- hydroxyphenyl)ethan- 1-one388.42 388.1

2-((3aR,5r,6aS)-5-(4- fluoro-2- methylbenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 385.44385.2

rac-(3aR,5r,6aS)-5-(4- fluoro-2- methylbenzyl)-2-(2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 387.46387.2

2-((3aR,6aS)-5-(2- fluoropyridin-3-yl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 358.38358.2

rac-5-(2,4- difluorobenzyl)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)octahydrocyclopenta[c] pyrrol-5-ol 390.18 390.5

rac-(3aR,5r,6aS)-5-(2- chlorobenzyl)-2-(2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 389.16389.1

2-((3aR,5r,6aS)-5- (2,3-difluorobenzyl)- 5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone 389.16389.2

rac-(3aR,5r,6aS)-5- (2,3-difluorobenzyl)- 2-(2-hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 391.18391.2

2-((3aR,5r,6aS)-5- (2,3-difluorobenzyl)- 5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 388.16 388.1

2-((3aR,5r,6aS)-5-(4- fluoro-2- methylbenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 384.46 384.2

rac-(3aR,6aS)-5-(2- fluoropyridin-3-yl)-2- (2-hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo penta[c]pyrrol-5-ol 360.39360.3

2-((3aR,5r,6aS)-5- (3,4-difluorobenzyl)- 5- hydroxyhexahydrocyclo-penta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 388.42 388.2

rac-(3aR,5r,6aS)-5- (3,4-difluorobenzyl)- 2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl) octahydrocyclopenta[c] pyrrol-5-ol 390.44 390.2

rac-(3aR,5r,6aS)-5-(4- fluoro-2- methylbenzyl)-2-(2- hydroxy-2-(4-hydroxyphenyl)ethyl) octahydrocyclopenta[c] pyrrol-5-ol 386.47 386.2

(3aR,5S,6aS)-5-(4- fluorobenzyl)-2-((S)- 2-hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 373.43373.2

(3aR,5R,6aS)-5-(4- fluorobenzyl)-2-((R)- 2-hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 373.43373.2

Example 37—Preparation of2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4′-hydroxy-[1,1′-biphenyl]-4-yl)ethanone

To a solution of2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-bromophenyl)ethanone(0.100 g, 0.24 mmol) and (4-hydroxyphenyl)boronic acid (0.040 g, 0.029mmol) in dioxane:water (3:1, 8 mL) was added potassium carbonate (0.099g, 0.72 mmol) and resulting mixture was degassed with nitrogen for 5minutes. To the above mixture was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.008 g, 0.012 mmol) and resulting suspension washeated at 100° C. under microwave irradiation for 30 minutes. Aftercompletion of reaction (as monitored by TLC), the reaction mixture wascooled to room temperature and diluted with water (10 mL). The solutionwas extracted with ethyl acetate (20 mL×2), the combined organic layerwas washed with water (50 mL), dried over sodium sulfate andconcentrated under vacuum to obtain crude material which was purified byprep HPLC affording the title compound2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4′-hydroxy-[1,1′-biphenyl]-4-yl)ethanone(5) (0.008 g, 8%) as off white solid. Calculated M+H: 428.21; Found M+H:428.12.

TABLE 12 The following compounds were prepared by the methods describedabove using intermediates made by the methods described above.Calculated Found Structure IUPAC Name M + H M + H

1-([1,1′-biphenyl]-4-yl)- 2-((3aR,5r,6aS)-5- benzyl-5-hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethanone 412.54 412.36

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(4′-methoxy-[1,1′- biphenyl]-4-yl)thanone442.23 442.10

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(2′-methyl-[1,1′- biphenyl]-4-yl)ethanone426.24 426.12

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(3′-fluoro-[1,1′- biphenyl]-4-yl)ethanone430.21 430.10

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(4′-fluoro-[1,1′- biphenyl]-4-yl)ethanone430.21 430.12

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(4′-methoxy-[1,1′- biphenyl]-3-yl)ethanone442.23 442.12

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(3′-methyl-[1,1′- biphenyl]-4-yl)ethanone426.24 426.11

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(3′-methoxy-[1,1′- biphenyl]-4-yl)ethanone442.23 442.0

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(4-(pyridin-2- yl)phenyl)ethanone 413.22413.11

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2((1H)- yl)-1-(4-(pyridin-3- yl)phenyl)ethanone 413.22413.10

1-([1,1′-biphenyl]-3-yl)- 2-((3aR,5r,6aS)-5- benzyl-5-hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethanone 412.22 412.11

2-[5-hydroxy-5-(2- phenylethyl)- octahydrocyclopenta[c]pyrrol-2-yl]-1-(4- phenylphenyl)ethan-1- one 426.24 426.10

1-[4-(3- fluorophenyl)phenyl]-2- [5-hydroxy-5-(2- phenylethyl)-octahydrocyclopenta[c] pyrrol-2-yl]ethan-1-one 444.23 444.12

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(3′-fluoro-[1,1′- biphenyl]-3-yl)ethanone430.21 430.10

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(3-(pyridin-3- yl)phenyl)ethanone 413.22413.14

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(3′-methoxy-[1,1′- biphenyl]-3-yl)ethanone442.23 442.0

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(4′-fluoro-[1,1′- biphenyl]-3-yl)ethanone430.21 430.0

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(4′-hydroxy-[1,1′- biphenyl]-3-yl)ethanone428.21 428.10

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(3′-methyl-[1,1′- biphenyl]-3-yl)ethanone426.24 426.12

2-[5-hydroxy-5-(2- phenylethyl)- octahydrocyclopenta[c]pyrrol-2-yl]-1-[4-(3- methylphenyl)phenyl]eth- an-1-one 440.25 44.0

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(2′-methyl-[1,1′- biphenyl]-3-yl)ethanone426.24 426.11

2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-(4-(2- methoxypyrimidin-5-yl)phenyl)ethanone 444.22 444.21

Example 38—Preparation ofrac-(3aR,5R,6aS)-5-benzyl-2-[2-hydroxy-2-(4-hydroxyphenyl)propyl]-octahydrocyclopenta[c]pyrrol-5-ol

To a solution of2-(5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone(0.2 g, 0.57 mmol) in tetrahydrofuran (50 mL), 3M methyl magnesiumbromide in diethyl ether (0.94 mL, 2.84 mmol) was added at 0° C. and thereaction mixture was stirred at room temperature for 5 h under nitrogenatmosphere. The solution was quenched with saturated ammonium chloridesolution (20 mL) and extracted with ethyl acetate (300 mL×2). Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand evaporated under vacuum to get crude which was purified by silicagel flash column chromatography using 15% methanol in dichloromethane toafford the title compound (3 aR,5R,6aS)-5-benzyl-2-[2-hydroxy-2-(4-hydroxyphenyl)propyl]-octahydrocyclopenta[c]pyrrol-5-ol(0.025 g, 11.9%) as a brownish solid. Calculated (M+H): 368.48; Found(M+1): 368.3.

Example 39—Preparation of deuteratedrac-(3aR,6aS)-5-benzyl-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol

To a stirred solution of2-((3aR,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone(0.05 g, 0.142 mmol) in ethanol (10 mL), was added sodium borodeuteride(0.059 g, 1.42 mmol) at room temperature and stirred for 10 h. Aftercompletion of the reaction (as monitored by TLC), the reaction mixturewas concentrated under vacuum. The residue was diluted with water (10mL) and extracted with ethyl acetate (30 mL×3). The combined organiclayer was washed with water (10 mL×2), brine (15 mL), dried overanhydrous sodium sulfate and concentrated under vacuum to afford thecrude compound which was triturated with diethyl ether:pentane (1:1)mixture to obtain the title compound deuterated(3aR,6aS)-5-benzyl-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol(0.010 g, 20% yield) as off-white solid. Calculated M+H: 355.21; FoundM+H: 355.5.

Example 40—Preparation ofN-(5-(2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)pyridin-2-yl)acetamide

To a solution of2-(5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(6-chloropyridin-3-yl)ethanone (0.1 g, 0.268 mmol) in toluene (2 mL) and tert-butanol (2 mL)mixture was added potassium carbonate (0.11 g, 0.806 mmol) followed byacetamide (0.024 g, 0.403 mmol). The reaction mixture was purged withnitrogen gas for 10 minutes. Finally 4, 5-bis (diphenylphosphino)-9,9-dimethyl xanthene (0.031 g, 0.053 mmol) andtri(dibenzylideneacetone) dipalladium(0) (0.025 g, 0.026) were added.The reaction mixture was heated at 100° C. in CEM microwave for 1 h. Thesolution was diluted with water (100 mL) and extracted withdichloromethane (100 mL×2). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified by silica gel flash column chromatography using 80% ethylacetate in hexane to afford the title compound N-(5-(2-((3 aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)pyridin-2-yl)acetamide(0.045 g, 21.43% yield) as pale yellow solid. Calculated M+H: 394.48;Found M+H: 394.2

TABLE 13 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name (M + H) (M + H)

rac-N-(5-(2- ((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)pyridin- 2-yl)acetamide 396.49396.2

tert-butyl (5-(2-(5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)acetyl)pyridin-2- yl)carbamate 452.25 452.3

N-(5-(2-(5-benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)acetyl)pyridin-2- yl)pivalamide 461.08 461.12

rac-N-(5-(2-(5-benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)pyridin- 2-yl)pivalamide 438.27438.6

Example 41—Preparation ofrac-(3aR,5r,6aS)-5-benzyl-2-(2-(2,4-dichlorophenyl)-2-hydroxyethyl)octahydrocyclopenta[c]pyrrol-5-ol

To a solution of (3aR,5r,6aS)-5-benzyloctahydrocyclopenta[c]pyrrol-5-ol(0.040 g, 0.12 mmol) in dichloromethane (2 mL) was added2-(2,4-dichlorophenyl)oxirane (0.044 g, 0.21 mmol) and triethylamine(0.041 mL, 0.29 mmol) and resulting solution was stirred at roomtemperature for 18 h. After completion of reaction (monitored by TLC),reaction mixture was diluted with water (2 mL). The organic layer wasextracted with dichloromethane (5 mL×2), washed with brine (10 mL),dried over sodium sulfate and concentrated under vacuum to afford thecrude (3 aR,5r,6aS)-5-benzyl-2-(2-(2,4-dichlorophenyl)-2-hydroxyethyl)octahydrocyclopenta[c]pyrrol-5-olwhich was purified by prep HPLC (column: XSelect CSH C-18 Prep (19×250mm, 5 um), mobile phase: A—5 mM ammonium acetate, B-Acetonitrile, flowmode: gradient, flow: 15 ml/min, gradientT/% B: 0/30, 0.5/30, 15/90,21/90, 21.5/30, 26/30).

TABLE 14 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name (M + H) (M + H)

rac-(3aR,5r,6aS)-5-benzyl-2- (2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl) octahydrocyclopenta[c]pyr- rol-5-ol406.19 406.4

rac-(3aR,5r,6aS)-5-benzyl-2- (2-(4-fluorophenyl)-2-hydroxyethyl)octahydrocyclo- penta[c]pyrrol-5-ol 356.19 356.39

Example 42—Preparation of5-benzyl-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol

Step 1: Preparation of benzyl(3aR,6aS)-3′-phenyltetrahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxirane]-2(3H)-carboxylate

To stirred solution of (3aR,6aS,Z)-benzyl5-benzylidenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.2 g,0.60 mmol) in dichloromethane (prepared by the method described below),was added meta-Chloroperoxybenzoic acid (mCPBA) (0.41 g, 2.40 mmol) atroom temperature and stirred for 4 h. After completion of the reaction(monitored by TLC), the mixture was diluted with ethyl acetate (50 mL).The ethyl acetate layer was washed with 50% sodium bicarbonate solution(15 mL×2), water (15 mL), brine (15 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford the crudecompound, which was purified by preparative HPLC (Column: CHIRALPAK IA(250 mm×4.6 mm×5 μm), Mobile phase: n-Hexane: Ethanol (80:20), Flowrate: 1.0 mL/min) separated two isomers to obtain the title compoundbenzyl(3aR,6aS)-3′-phenyltetrahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxirane]-2(3H)-carboxylate(0.1 g, major isomer, 6.93 retention time, off white semi solid) and0.065 g of minor isomer, 10.29 retention time, off white semi solid).Calculated M+H: 350.17; Found M+H: 350.2.

Step-2: Preparation of(3aR,5r,6aS)-5-benzyloctahydrocyclopenta[c]pyrrol-5-ol

To a solution of benzyl (3aR,6aS)-benzyl3′-phenyltetrahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxirane]-2(3H)-carboxylate(major isomer from previous step, 6.93 retention time) (0.2 g, 0.57mmol) in ethanol (10 mL), was added 10% Pd/C (0.05 g) at roomtemperature. The reaction mixture was subjected to hydrogenation inballoon and stirred for 3 h. After completion of the reaction (monitoredby TLC), the mixture was filtered through celite and washed withmethanol. The filtrate was concentrated under vacuum to obtain the titlecompound (3aR,5r,6aS)-5-benzyloctahydrocyclopenta[c]pyrrol-5-ol (0.12 g(crude), 97% yield) as off white liquid. Calculated M+H: 218.15; FoundM+H: 218.2.

Step-3: Preparation of2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone

To a stirred solution of(3aR,5r,6aS)-5-benzyloctahydrocyclopenta[c]pyrrol-5-ol (0.11 g, 0.51mmol) in dimethyl formamide (10 mL), was added potassium carbonate (0.14g, 1.01 mmol) and 2-bromo-1-(4-hydroxyphenyl)ethanone (0.087 g, 0.40mmol) at room temperature and stirred for 6 h. After completion of thereaction (monitored by TLC), the reaction mixture was quenched with coldwater and extracted with ethyl acetate (50 mL×3). The combined organiclayer was washed with cold water (20 mL), brine (20 mL), dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford the crude compound which was purified by preparative HPLC(Column: CHIRALPAK IA (250 mm×4.6 mm×5 m), Mobile phase: nHexane:Ethanol (50:50), Flow rate: 1.0 mL/min) to obtain the title compound2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone(0.065 g, 36% yield) as a pale yellow solid. Calculated M+H: 352.18;Found M+H: 352.5.

Step 4: Preparation of(3aR,5R,6aS)-5-benzyl-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol&(3aR,5S,6aS)-5-benzyl-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol

To a stirred solution of2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone(0.04 g, 0.11 mmol) in ethanol (20 mL), was added sodium borohydride(0.043 g, 1.14 mmol) at room temperature and stirred for 2 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasconcentrated under vacuum and the residue was diluted with water (15 mL)and extracted with ethyl acetate (50 mL×3). The combined organic layerwas washed with brine (10 mL), dried over anhydrous sodium sulfate andconcentrated under vacuum to afford the crude compound which waspurified by preparative HPLC (Column: CHIRALPAK IA (250 mm×4.6 mm×5 m),Mobile phase: nHexane: Ethanol (50:50), Flow rate: 1.0 mL/min) to obtainthe title compound (3 aR,5R,6aS)-5-benzyl-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol(0.0052 g, 13% yield) as off-white solid. Calculated M+H: 354.20; FoundM+H: 354.2, and(3aR,5S,6aS)-5-benzyl-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)octahydrocyclopenta[c]pyrrol-5-ol(0.0044 g, 11% yield) as off-white solid. Calculated M+H: 354.20; FoundM+H: 354.3.

Example 43—Preparation ofrac-2-((3aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one

To a stirred solution of(3aR,5r,6aS)-5-benzyloctahydrocyclopenta[c]pyrrol-5-ol (0.15 g, 0.69mmol) in ethanol (10 mL), was added triethylamine (0.21 g, 2.07 mmol)and 2-bromo-1-(4-hydroxyphenyl)propan-1-one (0.174 g, 0.76 mmol) at roomtemperature. The reaction mixture was heated to 80° C. and stirred for 2h. After completion of the reaction (monitored by TLC), the mixture wasconcentrated under vacuum to afford the crude compound which waspurified by preparative TLC using 10% methanol/dichloromethane to obtainthe title compound 2-((3 aR,5r,6aS)-5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one(0.09 g, 35.6% yield) as off white solid. Calculated M+H: 366.20; FoundM+H: 366.3.

Example 44—Preparation of(3aR,6aS)-5-benzyl-N-(3-methoxyphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

Step 1: Preparation of (3aR,6aS,Z)-benzyl5-benzylidenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate &(3aR,6aS)-benzyl5-benzyl-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a stirred solution of (3aR,5r,6aS)-benzyl5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (4.48g, 12.78 mmol) in toluene was added p-Toluenesulfonic acid (2.67 g,14.06 mmol) at room temperature. The reaction mixture was heated to 110°C. and stirred for 1.5 h. After completion of the reaction (monitored byTLC), the reaction mixture was allowed to cool to room temperature anddiluted with ethyl acetate (250 mL). The ethyl acetate layer was washedwith 50% sodium bicarbonate solution (50 ml×3), water (50 mL), brine (25mL), dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to afford the crude compound, which was purified by silicagel column chromatography (20% ethyl acetate/hexane) to obtain the titlecompound (3aR,6aS,Z)-benzyl5-benzylidenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and(3aR,6aS)-benzyl5-benzyl-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(2.87 g, 66% yield) as a pale brown liquid (mixture of both thecompounds taken for next step). Calculated M+H: 334.17; Found M+H:334.2.

Step 2: Preparation of (3aR,6aS)-5-benzyloctahydrocyclopenta[c]pyrrole

To a solution of (3aR,6aS,Z)-benzyl5-benzylidenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and(3aR,6aS)-benzyl5-benzyl-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.6g, 1.8 mmol) in ethanol (30 mL), was added 10% Pd/C (0.3 g) at roomtemperature. The reaction mixture subjected to hydrogenation in balloonand stirred for 3 h. After completion of the reaction (monitored byTLC), the mixture was filtered through celite bed, washed with methanol.The filtrate was concentrated under vacuum to obtain the title compound(3aR,6aS)-5-benzyloctahydrocyclopenta[c]pyrrole (0.336 g, 92.8% yield)as a colorless liquid. Calculated M+H: 202.15; Found M+H: 202.2.

Step 3: Preparation of(3aR,6aS)-5-benzyl-N-(3-methoxyphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

To a solution of 5-benzyloctahydrocyclopenta[c]pyrrole (0.1 g, 0.49mmol) and triethylamine (0.151 g, 1.49 mmol) in dichloromethane (10 mL)was added 1-isocyanato-3-methoxybenzene (0.071 g, 0.59 mmol) at 0° C.The reaction mixture was allowed to warm to room temperature and stirredfor 12 h. After completion of the reaction (monitored by TLC), thereaction mixture was quenched with saturated sodium bicarbonate solution(15 mL) and extracted with dichloromethane (25 mL×3). The combinedorganic layer was washed with water (10 mL×3), brine (10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford the crude compound which was purified by silica columnchromatography (3% methanol/dichloromethane) to obtain the titlecompound(3aR,6aS)-5-benzyl-N-(3-methoxyphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide(0.11 g, 64.9% yield) as off-white solid. Calculated M+H: 351.20; FoundM+H: 351.3.

Example 45—Preparation ofrac-2-((3aR,6aS)-5-benzylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone

To a stirred solution of (3aR,6aS)-5-benzyloctahydrocyclopenta[c]pyrrole(0.1 g, 0.49 mmol) in dimethyl formamide (5 mL), was added potassiumcarbonate (0.20 g, 1.49 mmol) and 2-bromo-1-(4-hydroxyphenyl)ethanone(0.13 g, 0.59 mmol) at room temperature and stirred for 6 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasquenched with cold water and extracted with ethyl acetate (30 mL×3). Thecombined organic layer were washed with cold water (25 mL×2), brine (20mL), dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to afford crude2-((3aR,6aS)-5-benzylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanonewhich was purified by preparative HPLC (Method: Zorbax Eclipse Plus C18RHD (50 mm×2.1 mm×1.81 μm), Mobile phase (A): 0.01% TFA in water, Mobilephase (B): ACN Flow rate: 0.3 mL/min T/% B: 0/10, 2/90, 3.8/90, 4.2/10,5/10) to obtain the title compound2-((3aR,6aS)-5-benzylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethan-1-oneas a TFA salt (0.013 g, 7.8% yield) as off white solid. Calculated M+H:336.19; Found M+H: 336.5.

TABLE 15 The following compounds were prepared by the method describedabove Calculated Found Structure IUPAC Name (M + H) (M + H)

rac-2-((3aR,6aS)-5- benzylhexahydro- cyclopenta[c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl)pro- pan-1-one 350.20 350.3

2-{5-benzyl- octahydrocyclo- penta[c]pyrrol-2-yl}-1- (5-hydroxypyridin-2-yl)ethan-1-one 337.43 337.0

rac-6-(2-{5-benzyl- octahydrocyclo- penta[c]pyrrol-2-yl}-1-hydroxyethyl)pyridin- 3-ol 339.44 339.2

2-{5-benzyl- octahydrocyclo- penta[c]pyrrol-2-yl}-1- (3-fluoro-4-hydroxyphenyl)ethan- 1-one 354.43 354.5

rac-4-(2- ((3aR,6aS)-5- benzylhexahydro- cyclopenta[c]pyrrol-2(1H)-yl)-1- hydroxy- ethyl)phenol 338.2 338.2

Example 46—Preparation of (3aR,5r,6aS)-benzyl5-benzylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and(3aR,5s,6aS)-benzyl5-benzylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a stirred solution of (3aR,6aS)-5-benzyloctahydrocyclopenta[c]pyrrole(1.5 g, 7.46 mmol) in acetonitrile (20 ml), potassium carbonate (3.1 g,22.38 mmol) and benzyl carbonochloridate (1.6 mL, 11.19 mmol) were addedat 0° C. The reaction mixture was stirred at room temperature for 16 h.The suspension was diluted with ethyl acetate (25 mL), filtered andwashed with 25 mL ethyl acetate. The combined filtrate was dried overanhydrous sodium sulfate, filtered and evaporated in vacuum to affordcrude which was purified by chiral HPLC (analytical conditions: column:CHIRALPAK IA (250 mm×4.6 mm×5 μm), mobile phase: 0.01% DEA in IPA, flowrate: 0.5 mL/min) to afford the title compounds (3aR,5r,6aS)-benzyl5-benzylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2) (0.26 g,10.4%) as colourless liquid [Calculated (M+H): 336.44; Found (M+1):336.22] and (3aR,5s,6aS)-benzyl5-benzylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2A) (0.19 g,7.6%) as colourless liquid [Calculated (M+H): 336.44; Found (M+1):336.2]. The stereochemistry given to 2 and 2A are tentative and they arenot absolute.

TABLE 16 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name M + H M + H

rac-4-{2- [(3aR,5S,6aS)-5- benzyl- octahydrocyclo-penta[c]pyrrol-2-yl]-1- hydroxyethyl}-2- fluorophenol 356.45 356.3

rac-4-{2- [(3aR,5R,6aS)-5- benzyl- octahydrocyclo-penta[c]pyrrol-2-yl]-1- hydroxyethyl}-2- fluorophenol 356.45 356.5

2-[(3aR,5S,6aS)-5- benzyl- octahydrocyclo- penta[c]pyrrol-2-yl]-1- (4-hydroxyphenyl)eth- an-1- onefluorophenol 336.44 336.5

rac-4-{2- [(3aR,5S,6aS)-5- benzyl- octahydrocyclo-penta[c]pyrrol-2-yl]-1- hydroxyethyl}phenol 338.46 338.5

2-[(3aR,5R,6aS)-5- benzyl- octahydrocyclo- penta[c]pyrrol-2-yl]-1- (4-hydroxyphenyl)eth- an-1-one 336.44 336.2

rac-4-{2- [(3aR,5R,6aS)-5- benzyl- octahydrocyclo-penta[c]pyrrol-2-yl]-1- hydroxyethyl}phenol 338.46 338.3

2-[(3aR,5S,6aS)-5- benzyl- octahydrocyclo- penta[c]pyrrol-2-yl]-1-(3-fluoro-4- hydroxyphenyl)eth- an-1-one 354.43 354.5

2-[(3aR,5R,6aS)-5- benzyl- octahydrocyclo- penta[c]pyrrol-2-yl]-1-(3-fluoro-4- hdyroxyphenyl)eth- an-1-one 354.43 354.5

Example 47—Preparation ofrac-2-((3aR,6aS)-5-benzylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3-(trifluoromethyl)phenyl)ethanol

To a solution of (3aR,6aS)-5-benzyloctahydrocyclopenta[c]pyrrole (0.1 g,0.49 mmol) in dimethyl formamide (0.040 g, 0.19 mmol) in dichloromethane(2 mL) was added 2-(3-(trifluoromethoxy)phenyl)oxirane (0.044 g, 0.22mmol) and triethylamine (0.041 mL, 0.29 mmol) and resulting solution wasstirred at room temperature for 18 h. After completion of reaction(monitored by TLC), the reaction mixture was diluted with water (2 mL)and extracted with dichloromethane (5 mL×2), washed with brine (10 mL),dried over sodium sulfate and concentrated under vacuum to give thecrude2-((3aR,6aS)-5-benzylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(3-(trifluoromethyl)phenyl)ethanolwhich was purified by prep HPLC (column: XSelect CSH C-18 Prep (19×250mm,5 um), mobile phase: A-5 mM ammonium acetate, B— Acetonitrile, flowmode: gradient, flow: 15 ml/min, gradientT/% B: 0/30, 0.5/30, 15/90,21/90, 21.5/30, 26/30).

Example 48—Preparation of5-hydroxy-N-(4-methoxyphenyl)-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

-   -   Step-1: Preparation of (3aR,5s,6aS)-benzyl        5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate        (2A) & (3aR,5r,6aS)-benzyl        5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate        (2B)

To a stirred solution of (3aR,5r,6aS)-benzyl5-benzyl-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (4.0g, 11.3 mmol) in dichloromethane was added diethylaminosulfurtrifluoride (3.3 mL, 25.0 mmol) at room temperature and stirred for 16h. After completion of reaction (monitored by TLC), the reaction mixturewas diluted with water (100 mL), extracted with dichloromethane (100mL×3). Organic layer was washed with water (50 mL), brine (50 mL), driedover anhydrous sodium sulfate, filtered and evaporated to afford crudeproduct, which was purified by silica gel column chromatography (0-25%ethylacetate/hexane) to obtain the title compound (3aR,5s,6aS)-benzyl5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2A)(2.8 g, 70% yield) as a colorless semi solid. Calculated (M+H): 354.43;Found (M+1): 354.18 and (3aR,5r,6aS)-benzyl5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2B)(0.38 g, 9.5% yield) as colorless semi solid. Calculated (M+H): 354.18;Found (M+1): 354.2.

Step-2: Preparation of(3aR,5s,6aS)-5-benzyl-5-fluorooctahydrocyclopenta[c]pyrrole

To a stirred solution of (3aR,5s,6aS)-benzyl5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.92g, 2.6 mol) in ethanol (20 mL), was added 10% Pd/C (0.25 g) under N₂atmosphere. The reaction mixture was subjected to hydrogenation inballoon and stirred for 6 h. After completion of reaction (monitored byTLC), the mixture was filtered through celite bed, washed with methanol.The filtrate was concentrated under vacuum to obtain the title compound(3aR,5s,6aS)-5-benzyl-5-fluorooctahydrocyclopenta[c]pyrrole [0.62 g(crude)] as colorless semi solid. Calculated (M+H): 220.14; Found (M+H):220.2.

Step-3: Preparation of2-((3aR,5s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone

To a stirred solution of(3aR,5s,6aS)-5-benzyl-5-fluorooctahydrocyclopenta[c]pyrrole (0.1 g, 0.46mmol) in dimethylformamide (5 mL) was added potassium carbonate (0.12 g,0.91 mmol) and 2-bromo-1-(4-hydroxyphenyl)ethanone (0.078 g, 0.36 mmol)at room temperature. The reaction mixture was stirred at roomtemperature for 4 h. After completion of reaction (monitored by TLC),the mixture was diluted with cold water (10 mL) and extracted withethylacetate (30 mL×3). The combined organic layer was washed with coldwater (15 mL×2), brine (15 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford the crudecompound, which was purified by silica gel column chromatography (6%methanol/dichloromethane) to obtain the title compound2-((3aR,5s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone(0.035 g, 22% yield) as a pale yellow solid. Calculated (M+H): 354.18;Found (M+H): 354.2.

TABLE 17 The following compound was prepared by the method describedabove Calculated Found Structure IUPAC Name (M + H) (M + H)

4-(2-((3aR,5s,6aS)-5- benzyl-5- fluorohexahydrocyclo-penta[c]pyrrol-2(1H)-yl)-1- hydroxyethyl)phenol 354.18 354.4

Step-4: Preparation ofrac-4-(2-((3aR,5s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol

To a stirred solution of2-((3aR,5s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone(0.14 g, 0.3961 mmol) in ethanol was added sodium borohydride (0.14 g,3.96 mmol) at room temperature and stirred for 6 h. After completion ofreaction (monitored by TLC), the solvent was removed under vacuum andthe residue was diluted with water (20 mL) and extracted with ethylacetate (25 mL×3). The combined organic layer was washed with water (25mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to afford the crude compound which waspurified by column chromatography using preparative TLC (8%methanol/dichloromethane) to obtain the title compound4-(2-((3aR,5s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol(0.055 g, 39% yield) as a white solid. Calculated (M+H): 356.19; Found(M+H): 356.5.

TABLE 18 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name (M + H) (M + H)

rac-4-(2-((3aR,5r,6aS)-5- benzyl-5- fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1- hydroxyethyl)phenol 356.19 356.5

rac-4-((R)-2-((3aR,5S,6aS)-5- benzyl-5- fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1- hydroxyethyl)phenol 356.19 356.2

rac-4-((S)-2-((3aR,5R,6aS)-5- benzyl-5- fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1- hydroxyethyl)phenol 356.19 356.2

rac-4-(2-((3aR,5s,6aS)-5- benzyl-5- fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1- hydroxyethyl)-2-fluorophenol 374.19 374.5

Example 49—Preparation ofrac-4-(2-((3aR,5s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxypropyl)phenol

Step-1: Preparation ofrac-2-((3aR,5s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one

To a stirred solution of(3aR,5s,6aS)-5-benzyl-5-fluorooctahydrocyclopenta[c]pyrrole (0.31 g,1.41 mmol) in dimethylformamide (20 mL) was added potassium carbonate(0.39 g, 2.82 mmol) and 2-bromo-1-(4-hydroxyphenyl)propan-1-one (0.32 g,1.41 mmol) at room temperature and stirred for 4 h. After completion ofreaction (monitored by TLC), the mixture was diluted with cold water (30mL) and extracted with ethylacetate (50 mL×3). The combined organiclayer was washed with cold water (25 mL), brine (25 mL), dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford the crude compound which was purified by silica gel columnchromatography (4% methanol/dichloromethane) to obtain the titlecompound2-((3aR,5s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one(0.18 g, 36% yield) as off white solid. Calculated (M+H): 368.19; Found(M+H): 368.5.

Step-2: Preparation ofrac-4-(2-((3aR,5s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxypropyl)phenol

To a stirred suspension of lithium borohydride (0.044 g, 2.04 mmol), intetrahydrofuran (10 mL) was added2-((3aR,5s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one(0.075 g, 0.204 mmol) at room temperature and stirred for 12 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasquenched with ice water (10 mL) and extracted with ethyl acetate (30ml×3). The combined organic layer was washed with water (10 mL×3), brine(10 mL), dried over anhydrous sodium sulfate, filtered and concentratedto afford the crude compound, which was purified by silica gel columnchromatography (6% methanol/dichloromethane) to obtain the titlecompound 4-(2-((3 aR,5s,6aS)-5-benzyl-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxypropyl)phenol(0.035 g, 46% yield) as a white solid. Calculated (M+H): 370.21; Found(M+H): 370.5.

Example 50—Preparation ofrac-2-(5-hydroxy-5-phenethylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one

To a solution of 5-phenethyloctahydrocyclopenta[c]pyrrol-5-ol (0.10 g,0.43 mmol) and 2-bromo-1-(4-hydroxyphenyl)propan-1-one (0.12 g, 0.51mmol) in ethanol (2 mL) was added triethylamine (0.14 mL, 1.02 mmol) andthe resulting suspension was heated to 90° C. and stirred for 2 h. Aftercompletion of reaction (monitored by TLC), the reaction was allowed tocool to room temperature, diluted with ethyl acetate (5 mL), washed withwater (15 mL×2), dried over sodium sulfate and concentrated to affordthe crude2-(5-hydroxy-5-phenethylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-onewhich was purified by prep HPLC; (Method: Column: XSelect CSH C-18 Prep(19×250 mm,5 um), Mobile phase: A-5 mM ammonium Acetate, B-Acetonitrile,Flow mode: Gradient, Flow: 15 ml/min, T/% B: 0.0/30, 0.5/30, 15.0/90,21.0/90, 21.5/30, 26.0/30).

Example 51—Preparation ofrac-2-(1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-5-phenethyloctahydrocyclopenta[c]pyrrol-5-ol

To a solution of2-(5-hydroxy-5-phenethylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)propan-1-one(0.070 g, 0.19 mmol) in methanol (3 mL), was added NaBH4 (0.02 g, 0.47mmol) and the resulting suspension was stirred at room temperature for 2h. After completion of reaction (monitored by TLC), the reaction mixturewas concentrated under vacuum and the residue was dissolved in ethylacetate (20 mL). The organic layer was washed with brine (15 mL×2),dried over sodium sulfate and concentrated under vacuum to obtain crude2-(1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-5-phenethyloctahydrocyclopenta[c]pyrrol-5-ol,which was purified by prep HPLC; (Method: Column: XSelect CSH C-18 Prep(19×250 mm,5 um), Mobile phase: A-5 mM ammonium acetate, B-Acetonitrile,Flow mode: Gradient, Flow: 15 ml/min, T/% B: 0.0/30, 0.5/30, 15.0/90,21.0/90, 21.5/30, 26.0/30).

TABLE 19 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name M + H M + H

rac-2-(2-hydroxy-2-(4- hydroxyphenyl)ethyl)-5- phenethyloctahydrocyclo-penta[c]pyrrol-5-ol 368.21 368.22

Example 52—Preparation of1-(4-hydroxyphenyl)-2-[(5R)-5-(2-phenylethyl)-octahydrocyclopenta[c]pyrrol-2-yl]propan-1-one

To a solution of 5-phenethyloctahydrocyclopenta[c]pyrrole (0.035 g, 0.16mmol) and 2-bromo-1-(4-hydroxyphenyl)propan-1-one (0.036 g, 0.16 mmol)in acetonitrile (2 mL) was added Cs₂CO₃ (0.16 g, 0.49 mmol) and theresulting suspension was heated to 80° C. and stirred for 2 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasallowed to cool to room temperature and diluted with ethyl acetate (5mL). The resulting mixture was washed with water (15 mL×2), dried oversodium sulfate and concentrated to afford crude1-(4-hydroxyphenyl)-2-[(5R)-5-(2-phenylethyl)-octahydrocyclopenta[c]pyrrol-2-yl]propan-1-one,which was purified by prep HPLC; (Method: Column: XSelect CSH C-18 Prep(19×250 mm, 5 um), Mobile phase: A-5 mM ammonium Acetate,B-Acetonitrile, Flow mode: Gradient, Flow: 15 ml/min, T/% B: 0.0/30,0.5/30, 15.0/90, 21.0/90, 21.5/30, 26.0/30).

TABLE 20 The following compounds were prepared by the method describedabove Calculated Found Structure IUPAC Name M + H M + H

1-(4-hydroxyphenyl)-2-(5- phenethylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)ethanone 350.20 350.09

1-(4-hydroxyphenyl)-2- ((3aR,5r,6aS)-5- phenethylhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)ethanone 350.20 350.09

1-(4-hydroxyphenyl)-2- ((3aR,5r,6aS)-5- phenethylhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)propan-1-one 364.22 364.18

Example 53—Preparation of4-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol

Step 1: Preparation of2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone

2-bromo-1-(4-hydroxyphenyl) ethanone (0.107 g, 0.494 mmol) was added toa mixture of commercially available2-benzyloctahydropyrrolo[3,4-c]pyrrole (0.1 g, 0.494 mmol) and potassiumcarbonate (0.2 g, 1.48 mmol) in DMF (5 mL) at 0° C. and the reactionmixture was stirred at room temperature for 2 h. The suspension wasfiltered and the filtrate was evaporated. The crude material waspurified by combi flash purifier using 8% methanol in dichloromethane toafford the title compound2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone(0.12 g, 72% yield) as a white solid. Calculated M+H: 337.43; Found M+H:337.2.

Step 2: Preparation of4-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol

Sodium borohydride (0.112 g, 2.97 mmol) was added to a solution of2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethanone(0.1 g, 0.297 mmol) in methanol (5 mL) at 0° C. and the reaction mixturewas stirred at room temperature for 3 h. Then the reaction mixture wasevaporated and the residue was diluted with water and extracted withdichloromethane (30 mL×2). The combined organic extract was dried overanhydrous sodium sulfate and evaporated to dryness. The crude materialwas purified by preparative HPLC (analytical conditions: column: zorbaxXDB C18 (150 mm×4.6 mm×3.5 μm) mobile phase (A) 0.01% ammonia in water,mobile phase (B): acetonitrile, flow rate: 1.0 mL/min, T/% B: 0/20,10/70, 25/70, 27/20, 30/20) to afford4-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenolas a white solid (0.03 g, 30.0% yield). Calculated M+H: 339.44; FoundM+H: 339.5.

TABLE 21 The following compounds were prepared by the method describedabove. Calculated Found Structure IUPAC Name M + H M + H

2-(5- benzylhexahydro- pyrrolo[3,4-c]pyrrol- 2(1H)-yl)-1-(5-hydroxypyridin-2- yl)ethanone 338.42 338.5

rac-6-(2-(5- benzylhexahydro- pyrrolo[3,4-c]pyrrol- 2(1H)-yl)-1-hydroxyethyl)pyridin- 3-ol 340.43 340.4

2-(5- benzylhexahydro- pyrrolo[3,4-c]pyrrol- 2(1H)-yl)-1-(3- fluoro-4-hydroxyphenyl)eth- anone 355.42 355.4

rac-4-(2-(5- benzylhexahydro- pyrrolo[3,4-c]pyrrol- 2(1H)-yl)-1-hydroxyethyl)-2- fluorophenol 357.43 357.5

Example 54—Preparation of6-benzyl-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-2-azaspiro[3.3]heptan-6-ol

Step 1: Preparation of tert-butyl 3-methyleneazetidine-1-carboxylate

Potassium tert-butoxide (4.27 g, 37.96 mmol) was added to a suspensionof methyltriphenylphosphonium bromide (13.56 g, 37.96 mmol) intetrahydrofuran (80 mL) and the reaction mixture was heated at 70° C.for 4 h. Then the reaction mixture was cooled to 50° C. and added asolution of tert-butyl 3-oxoazetidine-1-carboxylate (5 g, 29.2 mmol) intetrahydrofuran (20 mL) and heated at 70° C. for 15 h. The reactionmixture was cooled to room temperature and evaporated to dryness. Thecrude material was purified by combiflash purifier using 4% ethylacetate in hexane to afford the title compound tert-butyl3-methyleneazetidine-1-carboxylate (4 g, 80% yield) as a colorlessliquid. ¹H NMR (400 MHz, CDCl₃) δ 4.98 (s, 2H), 4.47 (s, 4H), 1.45 (s,9H).

Step 2: Preparation of tert-butyl5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate

A solution trichloroacetyl chloride (3.32 mL, 29.56 mmol) in1,2-dimethoxyethane (10 mL) was added dropwise to a mixture oftert-butyl 3-methyleneazetidine-1-carboxylate (1 g, 5.91 mmol) andzinc-copper couple powder (2.32 g, 35.47 mmol) in diethyl ether (20 mL)at 0° C. The reaction mixture was stirred at room temperature for 15 h.The solution was poured into sodium carbonate solution (100 mL),filtered through celite and the filtrate was extracted with ethylacetate (100 ml×2). The combined organic extract was washed with brine,dried over anhydrous sodium sulfate and evaporated to afford the titlecompound tert-butyl5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1 g, crude) asa black gum. The crude material was directly taken for next step.

Step 3: Preparation tert-butyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate

A solution of tert-butyl5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 3.5 mmol)in dioxane (20 mL) was added drop wise to a suspension of zinc powder(0.7 g, 10.71 mmol) in acetic acid (20 mL) at 0° C. and the reactionmixture was stirred at room temperature for 15 h. Then the reactionmixture was filtered through celite, filtrate was basified with 33%sodium hydroxide solution and extracted with ethyl acetate (50 mL×2).The combined organic extract was washed with brine (50 mL), dried overanhydrous sodium sulfate and evaporated. The crude material was purifiedby combiflash purifier using 30% ethyl acetate in hexane to afford thetitle compound tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate(0.42 g, 58% yield) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ4.12 (s, 4H), 3.28 (s, 4H), 1.45 (s, 9H).

Step 4: Preparation of tert-butyl6-benzyl-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate

Benzyl magnesium chloride solution (8.75 mL, 8.75 mmol, 1 M in diethylether) was added drop wise to a solution of tert-butyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (0.37 g, 1.75 mmol) intetrahydrofuran (10 mL) at 0° C. and the reaction mixture was stirred atroom temperature for 3 h. The reaction mixture was cooled, quenched withsaturated ammonium chloride solution and extracted with ethyl acetate(50 mL×2). The combined organic extract was washed with brine (50 mL),dried over anhydrous sodium sulfate and evaporated. The crude materialwas purified by combiflash purifier using 30% ethyl acetate in hexane toafford the title compound tert-butyl6-benzyl-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (0.35 g, 69%yield) as a white solid. Calculated M+H: 304.40; Found M+H: 204.1(M-boc).

Step 5: Preparation of 6-benzyl-2-azaspiro[3.3]heptan-6-ol

Trifluoroacetic acid (1.0 mL) was added dropwise to a solution oftert-butyl 6-benzyl-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (0.2g, 0.66 mmol) in dichloromethane (50 mL) at 0° C. and the reactionmixture was stirred at room temperature for 3 h. The solution wasevaporated to dryness and the crude material was washed with 50% diethylether in hexane and dried to afford the title compound6-benzyl-2-azaspiro[3.3]heptan-6-ol (0.19 g, crude) as a yellow gum.Calculated M+H: 204.28; Found M+H: 204.2.

Step 6: Preparation of2-(6-benzyl-6-hydroxy-2-azaspiro[3.3]heptan-2-yl)-1-(4-hydroxyphenyl)ethanone

2-Bromo-1-(4-hydroxyphenyl) ethanone (0.129 g, 0.599 mmol) was added toa mixture of 6-benzyl-2-azaspiro[3.3]heptan-6-ol (0.19 g, 0.599 mmol)and potassium carbonate (0.33 g, 2.39 mmol) in N,N-dimethylformamide (5mL) at 0° C. and the reaction mixture was stirred at room temperaturefor 3 h. The reaction mixture was evaporated to dryness. The residue wasdiluted with water and extracted with ethyl acetate (50 mL×2). Thecombined organic extract was dried over anhydrous sodium sulfate andevaporated. The crude material was purified by combiflash purifier using8-10% methanol in dichloromethane to afford the title compound2-(6-benzyl-6-hydroxy-2-azaspiro[3.3]heptan-2-yl)-1-(4-hydroxyphenyl)ethanone(0.04 g, 20% yield) as a white solid. Calculated M+H: 338.41; Found M+H:338.3.

Step 7: Preparation of6-benzyl-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-2-azaspiro[3.3]heptan-6-ol

Sodium borohydride (0.033 g, 0.89 mmol) was added to a solution of2-(6-benzyl-6-hydroxy-2-azaspiro[3.3]heptan-2-yl)-1-(4-hydroxyphenyl)ethanone(0.03 g, 0.089 mmol) in methanol (5 mL) at 0° C. and the reactionmixture was stirred at room temperature for 3 h. Then solution wasevaporated, the residue was diluted with water and extracted withdichloromethane (30 mL×2). The combined organic extract was dried overanhydrous sodium sulfate and evaporated to dryness. The crude materialwas washed with pentane and dried to afford the title compound6-benzyl-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-2-azaspiro[3.3]heptan-6-ol(0.02 g, 65% yield) as a white solid. Calculated M+H: 340.43; Found M+H:340.2.

Example 55—Cell Assay

Cell Culture and plating: HEK293 cells expressing NR1/NR2B (Chantest,Cleveland, Ohio) were grown to 70-80% confluency as an adherentmonolayer in standard tissue culture flasks at 37° C., 5% CO₂ persupplier's instructions. NR2B expression was induced by incubation with0.3-0.4 μg/ml tetracycline in the presence of 4 mM ARL-15896 for 18-24hours under the same growth conditions, then transferred to 30° C. foranother 3-5 hours.

After induction, cell culture medium was removed and cells were rinsedonce with Ca²⁺ and Mg²⁺-free Dulbecco's phosphate buffered saline. Cellswere then removed from the flask using TrypLE™ Express (LifeTechnologies) according to the manufacturer's instructions and collectedto 50 ml centrifuge tubes. Following two washes in Ca²⁺/Mg²⁺-free HBSSwith 20 mM HEPES (HHnoCa), cells were counted and viability assessedusing trypan blue. To load cells with Ca²⁺-sensitive dye, they wereresuspended in fluo-8 plus Component B (AAT Bioquest Products) dilutedin HHnoCa and incubated 15 minutes at 37° C., followed by 30 minutes atroom temp (in dark). Cells were then washed and resuspended in HHnoCa toremove extracellular dye and plated in 384-well plates (Falcon,uncoated) at 20,000-30,000 cells/well in a final volume of 25 μl/well.

FDSS Assay: To each well of the plate, 10 μL test compound, control(MK801) or HHnoCa buffer was added to a final concentration of 10 μMwith a final concentration of DMSO of 0.1%. Following 10 minutespre-incubation in the dark, plates are loaded onto the Hamamatsu FDSS6000. After collecting baseline fluorescence images, 3 μM glutamate, 3μM glycine, and 1 mM Ca²⁺ in HHnoCa buffer is added to each well, andCa²⁺ is recorded for 3 minutes. Data were processed by computing ratioof fluorescence at the end of data collection to baseline fluorescenceto assess degree of Ca²⁺ influx inhibition relative to that observed inMK801.

Table 30 below provides activity of each compound according to thelegend that “++++” indicates inhibition at a concentration <100 nM;“+++” indicates inhibition at a concentration between 100 nM and 1 μM ofthe disclosed compound; “++” indicates inhibition at a concentration offrom 1 μM to 10 μM; and “+” indicates inhibition at a concentration >10μM.

TABLE 22 illustrates the NR2B biological activities of the certaincompounds NR2B Cmpd NAM Binned # Structure IUPAC Name IC50 Activity 1

5-hydroxy-N-(4- methoxyphenyl)-5- phenylhexahydrocyclo-penta[c]pyrrole-2(1H)- carboxamide 1.00E- 05 + 2

5-(4-cyanophenyl)-5- hydroxy-N-(4- methoxyphenyl)-octahydrocyclopenta[c] pyr- role-2-carboxamide 1.00E- 05 + 3

5-hydroxy-N-(4- methylphenyl)-5-phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 4

N-(3-chlorophenyl)-5- hydroxy-5-phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 5

5-hydroxy-5-phenyl-N- [3- (trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 6

N-(4-fluorophenyl)-5- hydroxy-5-phenyl- octahydrocyclopenta[c]pyr-role-2-carboxmaide 1.00E- 05 + 7

5-hydroxy-N-(3- methoxyphenyl)-5- phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 8

5-hydroxy-N-(4- methoxyphenyl)-5-(2- methylphenyl)-octahydrocyclopenta[c]pyr- role-2-carobxamide 1.00E- 05 + 9

5-hydroxy-5-(2- methylphenyl)-N-(4- methylphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 10

5-hydroxy-N-(3- methoxyphenyl)-5-(2- methylphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 11

N-(3-chloro-phenyl)-5- hydroxy-5-(2- methylphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 12

5-hydroxy-5-(2- methylphenyl)-N-[3- (trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 13

N-(4-fluorophenyl)-5- hydroxy-5-(2- methylphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 14

5-hydroxy-5-(3- methoxyphenyl)-N-(4- methylphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 15

N-(3-chlorophenyl)-5- hydroxy-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 16

5-hydroxy-5-(3- methoxyphenyl)-N-[3- (trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 17

5-hydroxy-5-(3- methoxyphenyl)-N-(4- methoxyphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 18

5-hydroxy-N,5-bis(3- methoxyphenyl)- octahydrocyclopenta[c]pyr-role-2-carboxmaide 1.00E- 05 + 19

N-(2,4-difluorophenyl)-5- hydroxy-5-phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 20

N-[(1R)-1-(4- chlorophenyl)ethyl]-5- hydroxy-5-phenyl-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 21

5-hydroxy-N-[(2- methoxyphenyl)methyl]- 5-phenyl-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 22

Methyl 4-(5-hydroxy-5- (o- tolyl)octahydrocyclo- penta[c]pyrrole-2-carboxamido)benzoate 1.00E- 05 + 23

5-hydroxy-N-(2- methoxy-5- methylphenyl)-5-(2- methylphenyl)-octahydrocyclo- penta[c]pyrrole-2- carboxamide 1.00E- 05 + 24

N-[4-chloro-3- (trifluoromethyl)phenyl]- 5-hydroxy-5-(2- methylphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 25

5-hydroxy-N,5-diphenyl- octahydrocyclopenta[c]pyr- role-2-carboxamide1.00E- 05 + 26

N-(3-cyanophenyl)-5- hydroxy-5-phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 27

5-hydroxy-N-(2- methoxy-5- methylphenyl)-5-phenyl-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 28

methyl 4-[({5-hydroxy-5- phenyl- octahydrocyclo- penta[c]pyrrol-yl}carbonyl)amino]benzo- ate 1.00E- 05 + 29

5-hydroxy-5-(3- methoxyphenyl)-N- phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 30

5-hydroxy-5-(2- methylphenyl)-N-phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 31

N-(3-cyanophenyl)-5- hydroxy-5-(2- methylphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 32

N-[4-chloro-3- (trifluoromethyl)phenyl]- 5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 33

5-hydroxy-N-(2- methoxy-5- methylphenyl)-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 34

N-[4-chloro-3- (trifluoromethyl)phenyl]- 5-hydroxy-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 35

N,5-bis(4-fluorophenyl)- 5-hydroxy- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 36

5-(4-fluorophenyl)-5- hydroxy-N-(4- methylphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 37

5-(4-fluorophenyl)-5- hydroxy-N-(3- methoxyphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 38

5-(4-fluorophenyl)-5- hydroxy-N-[3- (trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 39

N-(3-chlorophenyl)-5-(4- fluorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 40

N-(3-cyanophenyl)-5-(4- fluorophenyl)-5-hydroxy-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 41

5-(4-fluorophenyl)-5- hydroxy-N-(pyridin-3- yl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 42

5-(4-fluorophenyl)-5- hydroxy-N-(2-methoxy- 5-methylphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 43

N-[4-chloro-3- (trifluoromethyl)phenyl]- 5-(4-fluorophenyl)-5- hydroxy-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 44

5-hydroxy-5-phenyl-N- (pyridin-3-yl)- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 45

methyl 4-({[5-hydroxy-5- (3-methoxyphenyl)- octahydrocyclopenta[c]pyr-rol-2- yl]carbonyl}amino)benzo- ate 1.00E- 05 + 46

5-hydroxy-5-(3- methoxyphenyl)-N- (pyridin-3-yl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 47

N-(2,4-dimethylphenyl)- 5-hydroxy-5-phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 48

N-(2,4-dimethylphenyl)- 5-hydroxy-5-(2- methylphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 49

N-(2,4-dimethylphenyl)- 5-hydroxy-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 50

methyl 4-({[5-(4-tert- butylphenyl)-5-hydroxy-octahydrocyclopenta[c]pyr- rol-2- yl]carbonyl}amino)benzo- ate 1.00E-05 + 51

5-(4-tert-butylphenyl)-5- hydroxy-N-(3- methoxyphenyl)-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 52

5-(4-tert-butylphenyl)-N- (3-cyanophenyl)-5- hydroxy-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 53

5-(4-tert-butylphenyl)-N- [4-chloro-3- (trifluoromethyl)phenyl]-5-hydroxy- octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 54

5-(4-tert-butylphenyl)-5- hydroxy-N-phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 55

5-(4-tert-butylphenyl)-5- hydroxy-N-[3- (trifluoromethyl)phenyl]-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 56

5-(4-tert-butylphenyl)-N- (3-chlorophenyl)-5- hydroxy-octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 + 57

2-(5-hydroxy-5- phenylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-phenylethanone 1.00E- 05 + 58

rac-2-(2-hydroxy-2- phenylethyl)-5- phenyloctahydrocyclo-penta[c]pyrrol-5-ol 1.00E- 05 + 59

2-[5-hydroxy-5-(3- methoxyphenyl)- octahydrocyclopenta[c]pyr-rol-2-yl]-1-phenylethan- 1-one 1.00E- 05 + 60

rac-2-(2-hydroxy-2- phenylethyl)-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyr- rol-5-ol 1.00E- 05 + 61

1-(3-fluorophenyl)-2-{5- hydroxy-5-phenyl- octahydrocyclopenta[c]pyr-rol-2-yl}ethan-1-one 1.00E- 05 + 62

1-(3-fluoropehnyl)-2-[5- hydroxy-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyr- rol-2-yl]ethan-1-one 1.00E- 05 + 63

rac-2-[2-(3- fluorophenyl)-2- hydroxyethyl]-5-(3- methoxyphenyl)-octahydrocyclopenta[c]pyr- rol-5-ol 1.00E- 05 + 64

rac-2-[2-(3- fluorophenyl)-2- hydroxyethyl]-5-phenyl-octahydrocyclopenta[c]pyr- rol-5-ol 1.00E- 05 + 65

2-{5-hydroxy-5-phenyl- octahydrocyclopenta[c]pyr- rol-2-yl}-1-(4-hydroxyphenyl)ethan-1- one 1.00E- 05 + 65

2-{5-hydroxy-5-phenyl- octahydrocyclopenta[c]pyr- rol-2-yl}-1-(4-methoxyphenyl)ethan-1- one 1.00E- 05 + 66

rac-2-[2-hydroxy-2-(4- methoxyphenyl)ethyl]-5- phenyl-octahydrocyclopenta[c]pyr- rol-5-ol 1.00E- 05 + 67

rac-2-[2-hydroxy-2-(4- hydroxyphenyl)ethyl]-5- phenyl-octahydrocyclopenta[c]pyr- rol-5-ol 1.00E- 05 + 68

2-(5-hydroxy-5- phenylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(4-(2-hydroxypropan-2- yl)phenyl)ethanone 1.00E- 05 + 69

rac-2-(2-hydroxy-2-(4- (2-hydroxypropan-2- yl)phenyl)ethyl)-5-phenyloctahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 70

rac-5-(4-(tert- butyl)phenyl)-2-(2- hydroxy-2-(3-(trifluoromethyl)phenyl)eth- yl)octahydrocyclo- penta[c]pyrrol-5-ol1.00E- 05 + 71

rac-5-(4-tert- butylphenyl)-2-[2-(3- fluorophenyl)-2- hydroxyethyl]-octahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 72

rac-2-{2-hydroxy-2-[3- (trifluoromethyl)phen- yl]ethyl}-5-(2-methylphenyl)- octahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 73

rac-2-{2-hydroxy-2-[3- (trifluorometh- yl)phenyl]ethyl}-5-(3-methoxyphenyl)- octahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 74

rac-2-[2-(2,4- dichlorophenyl)-2- hydroxyethyl]-5-(3- methoxyphenyl)-octahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 75

rac-5-(4-fluorophenyl)-2- {2-hydroxy-2-[3- (trifluoro-methyl)phenyl]ethyl}- octahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 76

rac-2-[2-(2,4- dichlorophenyl)-2- hydroxyethyl]-5-(4- fluorophenyl)-octahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 77

rac-2-[2-hydroxy-2-(3- methoxyphenyl)ethyl]-5- (3-methoxyphenyl)-octahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 78

rac-2-(1-hydroxy-1-(4- hydroxyphenyl)propan-2- yl)-5-(3-methoxyphenyl)octa- hydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 79

2-(4-fluorobenzyl)-5-(4- fluorophenyl)octahydro-cyclopenta[c]pyrrol-5-ol 1.00E- 05 + 80

5-(4-fluorophenyl)-2- (pyridin-2-yl)- octahydrocyclo-penta[c]pyrrol-5-ol 1.00E- 05 + 81

5-(4-fluorophenyl)-2-[6- (trifluoromethyl)pyridin- 2-yl]-octahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 82

5-(2-methylphenyl)-2- (pyridin-2-yl)- octahydrocyclo-penta[c]pyrrol-5-ol 1.00E- 05 + 83

5-phenyl-2-[6- (trifluoromethyl)pyridin- 2-yl]- octahydrocyclo-penta[c]pyrrol-5-ol 1.00E- 05 + 84

5-(2-methylphenyl)-2-[6- (trifluoromethyl)pyridin- 2-yl]-octahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 85

2-(6-methylpyridin-2-yl)- 5-phenyl- octahydrocyclo- penta[c]pyrrol-5-ol1.00E- 05 + 86

5-(2-methylphenyl)-2-(6- methylpyridin-2-yl)- octahydrocyclo-penta[c]pyrrol-5-ol 1.00E- 05 + 87

5-(4-fluorophenyl)-2-(6- methylpyridin-2-yl)- octahydrocyclo-penta[c]pyrrol-5-ol 1.00E- 05 + 88

5-(4-tert-butylphenyl)-2- (pyridin-2-yl)- octahydrocyclo-penta[c]pyrrol-5-ol 1.00E- 05 + 89

5-(4-tert-butylphenyl)-2- (6-methylpyridin-2-yl)- octahydrocyclo-penta[c]pyrrol-5-ol 1.00E- 05 + 90

rac-2-(5-hydroxy-5- phenylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl)propan-1- one 1.00E- 05 + 91

rac-2-(1-hydroxy-1-(4- hydroxyphenyl)propan-2- yl)-5-phenyloctahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 92

rac-2-[5-(4- fluorophenyl)-5-hydroxy- octahydrocyclopenta[c]pyr-rol-2-yl]-1-(4- hydroxyphenyl)propan-1- one 1.00E- 05 + 93

rac-2-[5-(4-tert- butylphenyl)-5-hydroxy- octahydrocyclopenta[c]pyr-rol-2-yl]-1-(4- hydroxyphenyl)propan-1- one 1.00E- 05 + 94

rac-2-[5-hydroxy-5-(2- methylphenyl)- octahydrocyclopenta[c]pyr-rol-2-yl]-1-(4- hydroxyphenyl)propan-1- one 1.00E- 05 + 95

rac-2-[1-hydroxy-1-(4- hydroxyphenyl)propan-2- yl]-5-(2-methylphenyl)-octahydrocyclopenta[c]pyr- rol-5-ol 1.00E- 05 + 96

rac-5-(4-tert- butylphenyl)-2-[1- hydroxy-1-(4- hydroxyphenyl)propan-2-yl]- octahydrocyclopenta[c]pyr- rol-5-ol 1.05E- 05 + 97

3-(5-hydroxy-5- phenylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1- (4-hydroxyphenyl)propan-1- one 1.00E- 05 + 98

2-(3-hydroxy-3-(4- hydroxyphenyl)propyl)- 5- phenyloctahydrocyclo-penta[c]pyrrol-5-ol 1.00E- 05 + 99

2 N-(4-methoxyphenyl)- 5- phenylhexahydrocyclo- penta[c]pyrrole-2(1H)-carboxamide 1.00E- 05 + 100

N-(4-hydroxyphenyl)-5- phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 101

N-(4-fluorophenyl)-5- phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 102

N,5-diphenyl- octahydrocyclopenta[c]pyr- role-2-carboxamide 1.00E- 05 +103

methyl 4-[({5-phenyl- octahydrocyclo- penta[c]pyrrol-2-yl}carbonyl)amino]benzo- ate 1.00E- 05 + 104

N-(3-methoxphenyl)-5- phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 105

5-phenyl-N-[3- (trifluoromethyl)phenyl]- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 106

N-(3-chlorophenyl)-5- phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 107

N-(3-cyanophenyl)-5- phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 108

N-[4-chloro-3- (trifluoromethyl)phenyl]- 5-phenyl-octahydrocyclopenta[c]pyr- role-2-carboxmaide 1.00E- 05 + 109

N-(2-methoxy-5- methylphenyl)-5-phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 110

N-(2,4-dimethylphenyl)- 5-phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 111

5-phenyl-N-(pyridin-3- yl)- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 112

N-[(2- methoxyphenyl)methyl]- 5-phenyl- octahydrocyclopenta[c]pyr-role-2-carboxmaide 1.00E- 05 + 113

N-[(1R)-1-(4- chlorophenyl)ethyl]-5- phenyl- octahydrocyclopenta[c]pyr-role-2-carboxamide 1.00E- 05 + 114

1-(4-hydroxyphenyl)-2- (5- phenylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)ethanone 2.32E- 07 +++ 115

4-(1-hydroxy-2-(5- phenylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)ethyl)phenol 1.00E- 05 + 116

rac-2-(5- phenylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1- (3-(trifluoromethyl)phenyl) ethanol 1.00E- 05 + 117

rac-1-(3- methoxyphenyl)-2-{5- phenyl- octahydrocyclopenta[c]pyr-rol-2-yl}ethan-1-ol 1.00E- 05 + 118

(3aR,5r,6aS)-5-benzyl-N- (3-chlorophenyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrole-2(1H)- carboxamide 1.00E- 05 + 119

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(3- methoxyphenyl)hexa-hydrocyclopenta[c]pyrrole- 2(1H)-carboxamide 1.00E- 05 + 120

(3aR,5r,6aS)-5-benzyl-N- (4-chloro-3- (trifluoromethyl)phenyl)- 5-hydroxyhexahydrocyclo- penta[c]pyrrole-2(1H)- carboxamide 1.00E- 05 +121

(3aR,5r,6aS)-5-benzyl-N- (2,4-dimethylphenyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrole-2(1H)- carboxamide 1.00E- 05 + 122

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N- phenylhexahydrocyclo-penta[c]pyrrole-2(1H)- carboxamide 1.00E- 05 + 123

(3aR,5r,6aS)-5-benzyl-N- (3-cyanophenyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrole-2(1H)- carboxamide 1.00E- 05 + 124

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(2-methoxy- 5-methylphenyl)hexahydro- cyclopenta[c]pyrrole- 2(1H)-carboxamide 1.00E-05 + 125

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(p- tolyl)hexahydrocyclo-penta[c]pyrrole-2(1H)- carboxamide 1.00E- 05 + 126

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(4- methoxyphenyl)hexahydro-cyclopenta[c]pyrrole- 2(1H)-carboxamide 1.00E- 05 + 127

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(2-(tri- fluoromethyl)phenyl)hexa-hydrocyclopenta[c]pyr- role-2(1H)-carboxamide 1.00E- 05 + 128

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(2- methoxyphenyl)hexahydro-cyclopenta[c]pyrrole- 2(1H)-carboxamide 1.00E- 05 + 129

(3aR,5r,6aS)-5-benzyl-5- hydroxy-N-(m- tolyl)hexahydrocyclo-penta[c]pyrrole-2(1H)- carboxamide 1.00E- 05 + 130

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 4.41E- 08 ++++131

rac-(3aR,5r,6aS)-5- benzyl-2-(2-hydroxy-2- (4- hydroxyphenyl)ethyl)octa-hydrocyclopenta[c]pyrrol- 5-ol 2.55E- 08 ++++ 132

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- methoxyphenyl)ethanone 1.00E- 05 + 133

3-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)propan-1- one 7.05E- 06 ++134

2-((3aR,5r,6aS)-5-(4- fluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 4.32E- 08 ++++135

rac-(3aR,5r,6aS)-5-(4- fluorobenzyl)-2-(2- hydroxy-2-(4-hydroxyphenyl)ethyl)octa- hydrocyclopenta[c]pyrrol- 5-ol 2.71E- 08 ++++136

(3aR,5R,6aS)-5-benzyl-2- ((R)-2-hydroxy-2-(4- hydroxyphenyl)ethyl)octa-hydrocyclopenta[c]pyrrol- 5-ol 2.37E- 08 ++++ 137

(3aR,5S,6aS)-5-benzyl-2- ((S)-2-hydroxy-2-(4- hydroxyphenyl)ethyl)octa-hydrocyclopenta[c]pyrrol- 5-ol 2.04E- 08 ++++ 138

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4-(2-hydroxypropan-2- yl)phenyl)ethanone1.00E- 05 + 139

rac-(3aR,5r,6aS)-5- benzyl-2-(2-hydroxy-2- (4-(2-hydroxypropan-2-yl)phenyl)ethyl)octahydro- cyclopenta[c]pyrrol-5-ol 1.00E- 05 + 140

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 6.94E- 06++ 141

N-(4-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)acetyl)phenyl)acetamide 1.00E- 05 + 142

(3aR,5R,6aS)-5-benzyl-2- ((R)-2-hydroxy-2-(4- hydroxyphenyl)ethyl)octa-hydrocyclopenta[c]pyrrol- 5-ol 2.37E- 08 ++++ 143

(3aR,5S,6aS)-5-benzyl-2- ((S)-2-hydroxy-2-(4- hydroxyphenyl)ethyl)octa-hydrocyclopenta[c]pyrrol- 5-ol 2.04E- 08 ++++ 144

rac-(3aR,5r,6aS)-5- benzyl-2-(2-hydroxy-2- (5-hydroxypyridin-2-yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 2.68E- 08 ++++ 145

1-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 3-(4- hydroxyphenyl)propan-2- one 1.00E- 05 +146

N-(4-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)acetyl)phenyl)methane- sulfonamide 3.26E- 07+++ 147

5-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)acetyl)indolin-2-one 3.52E- 07 +++ 148

6-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)acetyl)-3,4- dihydroquinolin-2(1H)- one 1.37E-07 +++ 149

rac-N-(4-(2- ((3aR,5r,6aS)-5-benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1- hydroxyethyl)phenyl)acet- amide 2.31E- 06++ 150

rac-N-(4-(2- ((3aR,5r,6aS)-5-benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1- hydroxyethyl)phenyl)meth- anesulfonamide4.70E- 08 ++++ 151

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(3-fluoro-4- hydroxyphenyl)ethanone 3.72E-07 +++ 152

rac-5-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)indolin- 2-one 1.43E- 07 +++153

rac-6-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4- dihydroquinolin-2(1H)-one 4.02E- 08 ++++ 154

rac-6-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1- hydroxyethyl)benzo[d]ox- azol-2(3H)-one5.24E- 08 ++++ 155

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(6-chloropyridin-3- yl)ethanone 1.00E- 05 +156

(3aR,5s,6aS)-5-benzyl-2- ((S)-2-(3-fluoro-4- hydroxyphenyl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol-5-ol 3.05E- 08 ++++ 157

6-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)acetyl)pyridazin- 3(2H)-one 1.00E- 05 + 158

rac-6-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1- hydroxyethyl)pyridazin- 3(2H)-one 1.00E-05 + 159

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(3,5-difluoro-4- hydroxyphenyl)ethanone1.16E- 05 + 160

rac-(3aR,5r,6aS)-5- benzyl-2-(2-(3,5-difluoro- 4-hydroxyphenyl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol-5-ol 9.81E- 08 ++++ 161

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(6-methoxypyridin-3- yl)ethanone 1.00E- 05 +162

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-(benzyloxy)pyrazin- 2-yl)ethanone 1.00E-05 + 163

rac-(3aR,5r,6aS)-5- benzyl-2-(2-(5- (benzyloxy)pyrazin-2-yl)- 2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol-5-ol 1.00E- 05 + 1646

(3aR,5S,6aS)-5-benzyl-2- ((S)-2-hydroxy-2-(5- hydroxypyridin-2-yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 3.81E- 08 ++++ 165

(3aR,5R,6aS)-5-benzyl-2- ((R)-2-hydroxy-2-(5- hydroxypyridin-2-yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 3.37E- 08 ++++ 166

2-((3aR,5r,6aS)-5-(4- fluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 6.40E- 06++ 167

2-[(3aR,5R,6aS)-5- benzyl-5-hydroxy- octahydrocyclopenta[c]pyr-rol-2-yl]-1-(1H-1,2,3- benzotriazol-5-yl)ethan- 1-one 1.00E- 05 + 168

rac-(3aR,5r,6aS)-5-(4- fluorobenzyl)-2-(2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 1.78E- 08++++ 169

1-(3-fluoro-4- hydroxyphenyl)-2- ((3aR,5r,6aS)-5-(4- fluorobenzyl)-5-hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethanone 1.17E- 07 +++170

2-((3aR,5r,6aS)-5-benzyl- 5- methoxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(3-fluoro-4- hydroxyphenyl)ethanone 1.32E-07 +++ 171

rac-(3aR,5r,6aS)-2-(2-(3- fluoro-4-hydroxyphenyl)- 2-hydroxyethyl)-5-(4-fluorobenzyl)octahydro- cyclopenta[c]pyrrol-5-ol 2.21E- 08 ++++ 172

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(3-fluoro-4-(2-(3- fluoro-4-hydroxyphenyl)-2- oxoethoxy)phenyl)ethanone 1.00E- 05 + 173

2-(2-fluoro-4-(2- ((3aR,5r,6aS)-5-(4- fluorobenzyl)-5-hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)- yl)acetyl)phenoxy)-1-(3-fluoro-4- hydroxyphenyl)ethanone 1.00E- 05 + 174

2-((3aR,5r,6aS)-5-benzyl- 5- methoxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 5.72E- 08 ++++175

rac-4-(2-((3aR,5r,6aS)-5- benzyl-5- methoxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-2- fluorophenol 3.24E- 08 ++++176

rac-4-(2-((3aR,5r,6aS)-5- benzyl-5- methoxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)phenol 3.24E- 08 ++++ 177

rac-6-(2-((3aR,5r,6aS)-5- benzyl-5- methoxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)pyridin- 3-ol 3.16E- 08 ++++178

2-[(3aR,5R,6aS)-5- benzyl-5-hydroxy- octahydrocyclopenta[c]pyr-rol-2-yl]-1-(6- hydroxypyridin-3- yl)ethan-1-one 1.00E- 05 + 179

2-((3aR,5r,6aS)-5- hydroxy-5-(4- methylbenzyl)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 7.98E- 08++++ 180

(3aR,5R,6aS)-5-benzyl-2- ((R)-2-(3-fluoro-4- hydroxyphenyl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol-5-ol 2.23E- 08 ++++

(3aR,5S,6aS)-5-benzyl-2- ((S)-2-(3-fluoro-4- hydroxyphenyl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol-5-ol 2.28E- 08 ++++ 181

rac-5-{2-[(3aR,5R,6aS)- 5-benzyl-5-hydroxy- octahydrocyclopenta[c]pyr-rol-2-yl]-1- hydroxyethyl}pyridin-2- ol 1.00E- 05 + 182

rac-(3aR,5R,6aS)-2-[2- hydroxy-2-(4- hydroxyphenyl)ethyl]-5- [(4-methylphenyl)methyl]- octahydrocyclopenta[c]pyr- rol-5-ol 4.15E- 08 ++++183

2-((3aR,5r,6aS)-5- hydroxy-5-(2- methylbenzyl)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 1.45E- 07+++ 184

2-[(3aR,5R,6aS)-5- hydroxy-5-[(4- methoxyphenyl)methyl]-octahydrocyclopenta[c]pyr- rol-2-yl]-1-(4- hydroxyphenyl)ethan-1- one4.33E- 08 ++++ 185

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)-5- (2-methylbenzyl)octahydro- cyclopenta[c]pyrrol-5-ol 3.49E- 08 ++++ 186

rac-(3aR,5R,6aS)-2-[2- (1H-1,2,3-benzotriazol-5- yl)-2-hydroxyethyl]-5-benzyl- octahydrocyclopenta[c]pyr- rol-5-ol 7.48E- 07 +++ 187

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyrazin-2- yl)ethanone 1.00E- 05 +188

rac-(3aR,5r,6aS)-5- benzyl-2-(2-hydroxy-2- (5-hydroxypyrazin-2-yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 + 189

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)-5- (4-methoxybenzyl)octahydro- cyclopenta[c]pyrrol-5-ol 4.74E- 08 ++++ 190

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(6-fluoro-5- hydroxypyridin-2- yl)ethanone1.00E- 05 + 191

rac-(3aR,5r,6aS)-5- benzyl-2-(2-(6-fluoro-5- hydroxypyridin-2-yl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol-5-ol 1.71E- 07 +++ 192

2-[(3aR,5R,6aS)-5- hydroxy-5-[(4- methoxyphenyl)methyl]-octahydrocyclopenta[c]pyr- rol-2-yl]-1-(5- hydroxypyridin-2-yl)ethan-1-one 7.61E- 06 ++ 193

2-((3aR,5r,6aS)-5- hydroxy-5-(3- methoxybenzyl)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(5- hydroxypyridin-2- yl)ethanone1.00E- 05 + 194

2-((3aR,5r,6aS)-5- hydroxy-5-(3- methoxybenzyl)hexahydro-cyclopenta[c]pyrrol- 2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 9.81E- 08++++ 195

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)-5- (3-methoxybenzyl)octahydro- cyclopenta[c]pyrrol-5-ol 2.87E- 08 ++++ 196

rac-((3aR,5r,6aS)-2-(2- hydroxy-2-(5- hydroxypyridin-2- yl)ethyl)-5-(3-methoxybenzyl)octahydro- cyclopenta[c]pyrrol-5-ol 6.60E- 08 ++++ 197

2-((3aR,5r,6aS)-5-benzyl- 5- methoxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(6-fluoro-5- hydroxypyridin-2- yl)ethanone1.00E- 05 + 198

rac-6-(2-((3aR,5r,6aS)-5- benzyl-5- methoxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-2- fluoropyridin-3-ol 4.76E-07 +++ 199

rac-6-{2-[(3aR,5R,6aS)- 5-hydroxy-5-[(4- methoxyphenyl)methyl]-octahydrocyclo- penta[c]pyrrol-2-yl]-1- hydroxyethyl}pyridin-3- ol3.63E- 08 ++++ 200

1-(6-fluoro-5- hydroxypyridin-2-yl)-2- ((3aR,5r,6aS)-5-hydroxy-5-(3-methoxy- benzyl)hexahydro- cyclopenta[c]pyrrol- 2(1H)-yl)ethanone1.00E- 05 + 201

rac-(3aR,5r,6aS)-2-(2-(6- fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5- (3- methoxybenzyl)octahydro-cyclopenta[c]pyrrol-5-ol 3.82E- 07 +++ 202

2-[(3aR,5R,6aS)-5- benzyl-5-hydroxy- octahydrocyclopenta[c]pyr-rol-2-yl]-1-(5- hydroxypyrimidin-2- yl)ethan-1-one 1.00E- 05 + 203

rac-2-{2-[(3aR,5R,6aS)- 5-benzyl-5-hydroxy- octahydrocyclopenta[c]pyr-rol-2-yl]-1- hydroxyethyl}pyrimidin- 5-ol 3.40E- 06 ++ 204

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)-5-(thiophen-2- ylmethyl)octahydrocyclo- penta[c]pyrrol-5-ol 1.26E- 08 ++++205

2-[(3aR,5R,6aS)-5- (cyclohexylmethyl)-5- hydroxy-octahydrocyclopenta[c]pyr- rol-2-yl]-1-(4- hydroxyphenyl)ethan-1- one3.46E- 07 +++ 206

2-[(3aR,5R,6aS)-5- (cyclohexylmethyl)-5- hydroxy- octahydrocyclo-penta[c]pyrrol-2-yl]-1-(5- hydroxypyridin-2- yl)ethan-1-one 1.00E- 05 +207

2-((3aR,5r,6aS)-5- (cyclopropylmethyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 1.00E- 05 +208

rac-6-{2-[(3aR,5R,6aS)- 5-[(3,5- dimethylphenyl)methyl]- 5-hydroxy-octahydrocyclo- penta[c]pyrrol-2-yl]-1- hydroxyethyl}pyridin-3- ol-3-ol6.66E- 07 +++ 209

rac-(3aR,5R,6aS)-5- (cyclohexylmethyl)-2-[2- hydroxy-2-(4-hydroxyphenyl)ethyl]- octahydrocyclo- penta[c]pyrrol-5-ol 4.10E- 07 +++210

2-((3aR,5r,6aS)-5- (cyclopropylmethyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 1.00E- 05 + 211

rac-(3aR,5r,6aS)-5- (cyclopropylmethyl)-2- (2-hydroxy-2-(4-hydroxyphenyl)ethyl)octa- hydrocycloprenta[c]pyrrol- 5-ol 1.00E- 05 +212

2-[(3aR,5R,6aS)-5-[(3,5- dimethylphenyl)methyl]- 5-hydroxy-octahydrocyclopenta[c]pyr- rol-2-yl]-1-(4- hydroxyphenyl)ethan-1- one1.00E- 5 + 213

rac-(3aR,5R,6aS)-5- [(3,5- dimethylphenyl)methyl]- 2-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]- octahydrocyclopenta[c]pyr- rol-5-ol 5.66E- 07 +++214

rac-6-{2-[(3aR,5R,6aS)- 5-(cyclohexylmethyl)-5- hydroxy-octahydrocyclopenta[c]pyr- rol-2-yl]-1- hydroxyethyl}pyridin-3- ol2.63E- 06 ++ 215

rac-2-(2-hydroxy-2-(5- hydroxypyridin-2- yl)ethyl)-5-(thiophen-2-ylmethyl)octahydrocyclo- penta[c]pyrrol-5-ol 2.57E- 08 ++++ 216

2-[(3aR,5R,6aS)-5- hydroxy-5-{[4- (trifluoro- methyl)phenyl]methyl}-octahydrocyclopenta[c]pyr- rol-2-yl]-1-(5- hydroxypyridin-2-yl)ethan-1-one 8.03E- 07 +++ 217

rac-6-{2-[(3aR,5R,6aS)- 5-hydroxy-5-{[4- (trifluoro-methyl)phenyl]methyl}- octahydrocyclopenta[c]pyr- rol-2-yl]-1-hydroxyethyl}pyridin-3- ol 3.60E- 08 ++++ 218

2-((3aR,5r,6aS)-5-(4- chlorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 3.74E- 07+++ 219

2-[(3aR,5R,6aS)-5- hydroxy-5-{[4- (trifluoro- methyl)phenyl]methyl}-octahydrocyclopenta[c]pyr- rol-2-yl]-1-(4- hydroxyphenyl)ethan-1- one1.25E- 07 +++ 220

1-(3-fluoro-4- hydroxyphenhyl)-2-(5- hydroxy-5-(thiophen-2-ylmethyl)hexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethanone 1.11E- 07 +++221

2-(5-(2-fluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 9.98E- 07+++ 222

rac-2-(2-(3-fluoro-4- hydroxyphenyl)-2- hydroxyethyl)-5- (thiophen-2-ylmethyl)octahydro- cyclopenta[c]pyrrol-5-ol 1.93E- 08 ++++ 223

rac-(3aR,5r,6aS)-5-(4- chlorobenzyl)-2-(2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 1.15E- 08++++ 224

rac-(3aR,5R,aS)-2-[2- hydroxy-2-(4- hydroxyphenyl)ethyl]-5- {[4-(trifluoro- methyl)phenyl]methyl}- octahydrocyclopenta[c]pyr- rol-5-ol8.48E- 08 ++++ 225

2-((3aR,5r,6aS)-5-(2- fluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 2.73E- 08 ++++226

2-((3aR,5r,6aS)-5- hydroxy-5-(pyridin-4- ylmethyl)hexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 3.89E- 06 ++ 227

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)-5- (pyridin-4-ylmethyl)octahydro- cyclopenta[c]pyrrol-5-ol 3.15E- 06 ++ 228

rac-5-(2-fluorobenzyl)-2- (2-hydroxy-2-(5- hydroxypyridin-2-yl)ethyl)octahydrocyclo- penta[c]pyrrol-5- olyl)ethanone 4.09E- 08 ++++229

rac-(3aR,5r,6aS)-5-(2- fluorobenzyl)-2-(2- hydroxy-2-(4-hydroxyphenyl)ethyl)octa- hydroxycyclopenta[c]pyrrol- 5-ol 1.55E- 08++++ 230

2-((3aR,5r,6aS)-5-(2,4- difluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 2.16E- 06++ 231

2-((3aR,5r,6aS)-5- hydroxy-5-(pyridin-2- ylmethyl)hexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 9.65E- 07 +++ 232

rac-(3aR,5r,6aS)-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)-5- (pyridin-2-ylmethyl)octahydrocyclo- penta[c]pyrrol-5-ol 6.69E- 07 +++ 233

rac-(3aR,5r,6aS)-5-(2,4- difluorobenzyl)-2-(2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 2.99E- 08++++ 234

2-((3aR,5r,6aS)-5-(2- chlorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 1.99E- 06++ 235

N-(6-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)acetyl)pyridin-3- yl)methanesulfonamide 1.00E-05 + 236

rac-N-(6-(2- ((3aR,5r,6aS)-5-benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)pyridin-3-yl)methanesulfonamide 1.14E- 07 +++ 237

2-[(3aR,5R,6aS)-5-[(2,6- difluorophenyl)methyl]- 5-hydroxy-octahydrocyclopenta[]pyr- rol-2-yl]-1-(5- hydroxypyridin-2-yl)ethan-1-one 1.91E- 06 ++ 238

2-(5-(2,4-difluorobenzyl)- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 5.16E- 08 ++++239

2-((3aR,5r,6aS)-5-(3,4- difluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 1.00E- 05 +240

rac-6-{2-[(3aR,5R,6aS)- 5-[(2,6- difluorophenyl)methyl]- 5-hydroxy-octahydrocyclopenta[c]pyr- rol-2-yl]-1- hydroxyethyl}pyridin-3- ol6.96E- 08 ++++ 241

2-[(3aR,5R,6aS)-5-[(2,6- difluorophenyl)methyl]- 5-hydroxy-octahydrocyclopenta[c]pyr- rol-2-yl]-1-(4- hydroxyphenyl)ethan-1- one1.18E- 07 +++ 242

2-((3aR,5r,6aS)-5-(4- fluoro-2-methylbenzyl)- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 2.71E- 06++ 243

rac-(3aR,5r,6aS)-5-(4- fluoro-2-methylbenzyl)- 2-(2-hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 7.57E- 08++++ 244

2-((3aR,6aS)-5-(2- fluoropyridin-3-yl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 1.00E- 05 +245

rac-5-(2,4- difluorobenzyl)-2-(2- hydroxy-2-(4-hydroxyphenyl)ethyl)octa- hydrocyclopenta[c]pyrrol- 5-ol 2.38E- 08 ++++246

rac-(3aR,5r,6aS)-5-(2- chlorobenzyl)-2-(2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 5.03E- 08++++ 247

2-((3aR,5r,6aS)-5-(2,3- difluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(5-hydroxypyridin-2- yl)ethanone 3.06E- 06++ 248

rac-(3aR,5r,6aS)-5-(2,3- difluorobenzyl)-2-(2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 4.76E- 08++++ 249

2-((3aR,5r,6aS)-5-(2,3- difluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 1.10E- 07 +++ 250

2-((3aR,5r,6aS)-5-(4- fluoro-2-methylbenzyl)- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 1.37E- 07 +++ 251

rac-(3aR,6aS)-5-(2- fluoropyridin-3-yl)-2-(2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 1.00E-05 + 252

2-((3aR,5r,6aS)-5-(3,4- difluorobenzyl)-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 8.53E- 08 ++++253

rac-(3aR,5r,6aS)-5-(3,4- difluorobenzyl)-2-(2- hydroxy-2-(4-hydroxyphenyl)ethyl)octa- hydroxycyclopenta[c]pyrrol- 5-ol 3.15E- 08++++ 254

rac-(3aR,5r,6aS)-5-(4- fluoro-2-methylbenzyl)- 2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)octa- hydrocyclopenta[c]pyrrol- 5-ol 4.25E- 08 ++++255

(3R,5S,6aS)-5-(4- fluorobenzyl)-2-((S)-2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 2.40E- 08++++ 256

(3aR,5R,6aS)-5-(4- fluorobenzyl)-2-((R)-2- hydroxy-2-(5-hydroxypyridin-2- yl)ethyl)octahydrocyclo- penta[c]pyrrol-5-ol 3.17E- 08++++ 257

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4′-hydroxy-[1,1′- biphenyl]-4-yl)ethanone1.00E- 05 + 258

1-([1,1′-biphenyl]-4-yl)- 2-((3aR,5r,6aS)-5-benzyl- 5-hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethanone 1.00E- 05 + 259

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4′-methoxy-[1,1′- biphenyl]-4-yl)ethanone1.00E- 05 + 260

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(2′-methyl-[1,1′- biphenyl]-4-yl)ethanone1.00E- 05 + 261

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(3′-fluoro-[1,1′- biphenyl]-4-yl)ethanone1.00E- 05 + 262

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4′-fluoro-[1,1′- biphenyl]-4-yl)ethanone1.00E- 05 + 263

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4′-methoxy-[1,1′- biphenyl]-3-yl)ethanone1.00E- 05 + 264

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(3′-methyl-[1,1′- biphenyl]-4-yl)ethanone1.00E- 05 + 265

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(3′-methoxy-[1,1′- biphenyl]-4-yl)ethanone1.00E- 05 + 266

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4-(pyridin-2- yl)phenyl)ethanone 1.00E-05 + 267

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4-(pyridin-3- yl)phenyl)ethanone 1.00E-05 + 268

1-([1,1′-biphenyl]-3-yl)- 2-((3aR,5r,6aS)-5-benzyl- 5-hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)- yl)ethanone 1.00E- 05 + 269

2-[5-hydroxy-5-(2- phenylethyl)- octahydrocyclopenta[c]pyr-rol-2-yl]-1-(4- phenylphenyl)ethan-1- one 1.00E- 05 + 270

1-[4-(3- fluorophenyl)phenyl]-2- [5-hydroxy-5-(2- phenylethyl)-octahydrocyclopenta[c]pyr- rol-2-yl]ethan-1-one 1.00E- 05 + 271

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(3′-fluoro-[1,1′- biphenyl]-3-yl)ethanone1.00E- 05 + 272

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(3-(pyridin-3- yl)phenyl)ethanone 1.00E-05 + 273

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(3′-methoxy-[1,1′- biphenyl]-3-yl)ethanone1.00E- 05 + 274

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4′-fluoro-[1,1′- biphenyl]-3-yl)ethanone1.00E- 05 + 275

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4′-hydroxy-[1,1′- biphenyl]-3-yl)ethanone1.00E- 05 + 276

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(3′-methyl-[1,1′- biphenyl]-3-yl)ethanone1.00E- 05 + 277

2-[5-hydroxy-5-(2- phenylethyl)- octahydrocyclopenta[c]pyr-rol-2-yl]-1-[4-(3- methylphenyl)phenyl]eth- an-1-one 1.00E- 05 + 278

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(2′-methyl-[1,1′- biphenyl]-3-yl)ethanone1.00E- 05 + 279

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4-(2- methoxypyrimidin-5-yl)phenyl)ethanone 1.00E- 05 + 280

rac-(3aR,5R,6aS)-5- benzyl-2-[2-hydroxy-2- (4- hydroxyphenyl)propyl]-octahydrocyclopenta[c]pyr- rol-5-ol 4.30E- 08 ++++ 281

deuterated rac-(3aR,6aS)- 5-benzyl-2-((S)-2- hydroxy-2-(4-hydroxyphenyl)ethyl)octa- hydrocyclopenta[c]pyrrol- 5-ol 1.74E- 08 ++++282

N-(5-(2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)acetyl)pyridin-2- yl)acetamide 1.00E- 05 + 283

rac-N-(5-(2- ((3aR,5r,6aS)-5-benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)pyridin- 2-yl)acetamide 1.00E-05 + 284

tert-butyl (5-(2-(5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)acetyl)pyridin-2- yl)carbamate 1.00E- 05 + 285

N-(5-(2-(5-benzyl-5- hydroxyhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)acetyl)pyridin-2- y)pivalamide 1.00E- 05 + 286

rac-N-(5-(2-(5-benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)pyridin- 2-yl)pivalamide 1.00E-05 + 287

rac-(3aR,5r,6aS)-5- benzyl-2-(2-(2,4- dichloropehnyl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol-5-ol 1.00E- 05 + 288

rac-(3aR,5r,6aS)-5- benzyl-2-(2-hydroxy-2- (3-(trifluoro-methyl)phenyl)eth- yl)octahydrocyclo- penta[c]pyrrol-5-ol 1.00E- 05 +289

rac-(3aR,5r,6aS)-5- benzyl-2-(2-(4- fluorophenyl)-2-hydroxyethyl)octahydro- cyclopenta[c]pyrrol-5-ol 1.00E- 05 + 290

2-((3aR,5r,6aS)-5-benzyl- 5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)ethanone 7.66E- 08 ++++2291

(3aR,5R,6aS)-5-benzyl-2- ((R)-2-hydroxy-2-(4- hydroxyphenyl)ethyl)octa-hydroxycyclo- penta[c]pyrrol-5-ol 3.32E- 07 +++ 292

(3aR,5S,6aS)-5-benzyl-2- ((S)-2-hydroxy-2-(4- hydroxyphenyl)ethyl)octa-hydroxycyclo- penta[c]pyrrol-5-ol 4.71E- 06 ++ 293

rac-2-((3aR,5r,6aS)-5- benzyl-5- hydroxyhexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)propan-1- one 1.00E- 07+++ 294

(3aR,6aS)-5-benzyl-N-(3- methoxyphenyl)hexa- hydrocyclopenta[c]pyrrol-2(1H)-carboxamide 1.00E- 05 + 295

2-((3aR,6aS)-5- benzylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)- 1-(4-hydroxyphenyl)ethanone 5.17E- 08 ++++ 296

rac-2-((3aR,6aS)-5- benzylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl)propan-1- one 1.25E- 07 +++ 297

2-{5-benzylocta- hydrocyclopenta[c]pyr- rol-2-yl}-1-(5-hydroxypyridin-2- yl)ethan-1-one 7.92E- 07 +++ 298

rac-6-(2-{5-benzyl- octahydrocyclopenta[c]pyr- rol-2-yl}-1-hydroxyethyl)pyridin-3- ol 2.24E- 08 ++++ 299

2-{5-benzyl- octahydrocyclopenta[c]pyr- rol-2-yl}-1-(3-fluoro-4-hydroxyphenyl)ethan-1- one 7.81E- 08 ++++ 300

rac-4-(2-((3aR,6aS)-5- benzylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol 1.39E- 08 ++++ 301

rac-4-{2-[(3aR,5S,6aS)- 5-benzyl- octahydrocyclopenta[c]pyr-rol-2-yl]-1- hydroxyethyl}-2- fluorophenol 1.22E- 08 ++++ 302

rac-4-{2-[(3aR,5R,6aS)- 5-benzyl- octahydrocyclopenta[c]pyr-rol-2-yl]-1- hydroxyethyl}-2- fluorophenol 2.01E- 08 ++++ 303

2-[(3aR,5S,6aS)-5- benzyl- octahydrocyclopenta[c]pyr- rol-2-yl]-1-(4-hydroxyphenyl)ethan-1- onefluorophenol 3.88E- 08 ++++ 304

rac-4-{2-[(3aR,5S,6aS)- 5-benzyl- octahydrocyclopenta[c]pyr-rol-2-yl]-1- hydroxyethyl}phenol 1.68E- 08 ++++ 305

2-[(3aR,5R,6aS)-5- benzyl- octahydrocyclopenta[c]pyr- rol-2-yl]-1-(4-hydroxyphenyl)ethan-1- one 5.35E- 08 ++++ 306

rac-4-{2-[(3aR,5R,6aS)- 5-benzyl- octahydrocyclopenta[c]pyr-rol-2-yl]-1- hydroxyethyl}phenol 1.17E- 08 ++++ 307

2-[(3aR,5S,6aS)-5- benzyl- octahydrocyclopenta[c]pyr-rol-2-yl]-1-(3-fluoro-4- hydroxyphenyl)ethan-1- one 4.12E- 08 ++++ 308

2-[(3aR,5R,6aS)-5- benzyl- octahydrocyclopenta[c]pyr-rol-2-yl]-1-(3-fluoro-4- hydroxyphenyl)ethan-1- one 5.22E- 08 ++++ 309

rac-2-((3aR,6aS)-5- benzylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(3- (trifluoromethyl)phenyl)eth- anol 1.00E- 05 + 310

2-((3aR,5s,6aS)-5- benzyl-5- fluorohexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl)ethanone 1.75E- 07 +++ 311

rac-4-(2-((3aR,5s,6aS)-5- benzyl-5- fluorohexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)phenol 4.48E- 07 +++ 312

4-(2-((3aR,5s,6aS)-5- benzyl-5- fluorohexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-hydroxyethyl)phenol 9.30E- 08 ++++ 313

rac-4-(2-((3aR,5r,6aS)-5- benzyl-5- fluorohexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)phenol 2.69E- 08 ++++ 314

4-((R)-2-((3aR,5S,6aS)- 5-benzyl-5- fluorohexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)phenol 4.14E- 07 +++ 315

4-((S)-2-((3aR,5R,6aS)- 5-benzyl-5- fluorohexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-hydroxyethyl)phenol 3.24E- 07 +++ 316

rac-4-(2-((3aR,5s,6aS)-5- benzyl-5- fluorohexahydrocyclo-penta[c]pyrrol-2(1H)- yl)-1-hydroxyethyl)-2- fluorophenol 3.64E- 08 ++++317

rac-2-((3aR,5s,6aS)-5- benzyl-5- fluorohexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-(4- hydroxyphenyl)propan-1- one 2.84E- 07+++ 318

rac-4-(2-((3aR,5s,6aS)-5- benzyl-5- fluorohexahydrocyclo-penta[c]pyrrol-2(1H)-yl)- 1-hydroxypropyl)phenol 1.28E- 05 + 319

rac-2-(5-hydroxy-5- phenethylhexahydrocyclo- penta[c]pyrrol-2(1H)-yl)-1-(4- hydroxyphenyl)propan-1- one 4.97E- 07 +++ 320

rac-2-(1-hydroxy-1-(4- hydroxyphenyl)propan-2- yl)-5-phenethyloctahydrocyclo- penta[c]pyrrol-5-ol 2.05E- 06 ++ 321

rac-2-(2-hydroxy-2-(4- hydroxyphenyl)ethyl)-5- phenethyloctahydrocyclo-penta[c]pyrrol-5-ol 1.00E- 05 + 322

rac-1-(4-hydroxyphenyl)- 2-[(5R)-5-(2- phenylethyl)-octahydrocyclopenta[c]pyr- rol-2-yl]propan-1-one 5.33E- 07 +++ 323

1-(4-hydroxyphenyl)-2- (5- phenethylhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)ethanone 4.26E- 07 +++ 324

1-(4-hydroxyphenyl)-2- ((3aR,5r,6aS)-5- phenethylhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)ethanone 2.15E- 07 +++ 325

1-(4-hydroxyphenyl)-2- ((3aR,5r,6aS)-5- phenethylhexahydrocyclo-penta[c]pyrrol-2(1H)- yl)propan-1-one 1.92E- 07 +++ 326

2-(5-benzyl- hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1- (4-hydroxyphenyl)ethanone 6.82E- 07 +++ 327

rac-4-(2-(5-benzyl- hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol 1.39E- 07 +++ 328

2-(5-benzyl- hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2- yl)ethanone 1.00E- 05 + 329

rac-6-(2-(5-benzyl- hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3- ol 3.80E- 07 +++ 340

2-(5-benzyl- hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1- (3-fluoro-4-hydroxyphenyl)ethanone 1.00E- 05 + 341

rac-4-(2-(5-benzyl- hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1-hydroxyethyl)-2- fluorophenol 7.43E- 08 ++++ 342

2-(6-benzyl-6-hydroxy-2- azaspiro[3.3]heptan-2- yl)-1-(4-hydroxyphenyl)ethanone 2.67E- 06 ++ 343

rac-6-benzyl-2-(2- hydroxy-2-(4- hydroxyphenyl)ethyl)-2-azaspiro[3.3]heptan-6-ol 5.06E- 07 +++

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1. A compound of Formula I:

or pharmaceutically acceptable salt, prodrug, solvate, hydrate,tautomer, or stereoisomer thereof wherein: L₁ is straight or branchedC₂-C₄ alkyl optionally substituted with one or more substituentsselected from the group consisting of OH, D, OR₁₀, NH₂, NHR₁₀, andN(R₁₀)(R_(10′)), provided that no more than one oxygen or nitrogen isattached to any carbon; or L₁ is selected from the group consisting of—CO—C₁-C₂alkylenyl-, —S(O)₂—, —S(O)₂NH—, —C(O)NH—, —C(O)NR₁₀—,—C₁-C₃alkylenyl-C(O)—C₁-C₃alkylenyl-, and a bond, wherein the C₁-C₂alkylenyl and C₁-C₃ alkylenyl is optionally substituted with C₁-C₄alkyl; each R₁₀ and R_(10′) is independently selected from the groupconsisting of H; O—C₁-C₅ alkyl; C₁-C₆ alkyl optionally substituted withone or more substituents selected from the group consisting of OH,O—C₁-C₅ alkyl, —OP(O)(OH)₂, OP(O)O₂ ⁻²M₂, —OC(O)alkyl, —OC(O)Oalkyl,aryl, and heteroaryl; and cycloalkyl optionally substituted with one ormore substituents selected from the group consisting of OH and O—C₁-C₅alkyl; provided that no more than one oxygen is attached to any carbonof R₁₀ and R_(10′); M is a monovalent metal cation; or R₁₀ and R_(10′),together with the nitrogen to which they are attached, may form aheterocycle; R₁ is aryl or heteroaryl, both of which optionallysubstituted with one or more substituents selected from the groupconsisting of OH, CN, halogen, —O—R₁₀, —OP(O)(OH)₂, OP(O)O₂ ⁻²M₂, —SH,—S—R₁₀, C₁-C₅ alkyl, branched alkyl, —C₁-C₆haloalkyl, NH₂, NHR₁₀,—C₁-C₆hydroxyalkyl, N(R₁₀)(NR_(10′)), —NHS(O)₂R₁₀, —O— alkylaryl,—O—(CH₂)_(n)—C(O)-aryl, and NHCOR₁₀; M is a monovalent metal cation; orR₁ is cycloalkyl; X is selected from the group consisting of H, halogen,OH, O—C₁-C₆ alkyl, O-branched alkyl, C₁-C₅ straight alkyl and C₁-C₅branched alkyl; Y and Y′ are independently H, F, or methyl; L₂ is—(CH₂)_(n)— or —(CHR₁₁)_(n)—, or a bond; each R₁₁ is independentlyselected from the group consisting of H, —C₁-C₅ alkylenyl-,—C(O)—C₁-C₅alkylenyl-, and -alkylenyl-CO-alkylenyl-; R₂ isC₃-C₈cycloalkyl; C₃-C₈heterocyclcyl, phenyl, naphthyl, heteroaryl, orbicyclic heteroaryl, each of which is optionally substituted with one ormore substituents selected from the group consisting of halogen, OH,C₁-C₆alkyl, OR₁₀, CN, NH₂, NHR₁₀, N(R₁₀)(R_(10′)), SH, SR₁₀, SOR₁₀,SO₂R₁₀, SO₂NHR₁₀, SO₂N(R₁₀)(R_(10′)), CONH₂, CONRd, andCON(R₁₀)(R_(10′)); and n is 1, 2, or
 3. 2-58. (canceled)